Distinct spectral dynamics of implanted cardiac defibrillator signals in spontaneous termination of polymorphic ventricular tachycardia and fibrillation in patients with electrical and structural diseases.

AIMS: To determine the spectral dynamics of early spontaneous polymorphic ventricular tachycardia and ventricular fibrillation (PVT/VF) in humans. METHODS AND RESULTS: Fifty-eight self-terminated and 173 shock-terminated episodes of spontaneously initiated PVT/VF recorded by Medtronic implanted cardiac defibrillators (ICDs) in 87 patients with various cardiac pathologies were analyzed by short fast Fourier transform of shifting segments to determine the dynamics of dominant frequency (DF) and regularity index (RI). The progression in the intensity of DF and RI accumulations further quantified the time course of spectral characteristics of the episodes. Episodes of self-terminated PVT/VF lasted 8.6 s [95% confidence interval (CI): 8.1-9.1] and shock-terminated lasted 13.9 s (13.6-14.3) (P < 0.001). Recordings from patients with primarily electrical pathologies displayed higher DF and RI values than those from patients with primarily structural pathologies (P < 0.05) independently of ventricular function or antiarrhythmic drug therapy. Regardless of the underlying pathology, the average DF and RI intensities were lower in self-terminated than shock-terminated episodes [DF: 3.67 (4.04-4.58) vs. 4.32 (3.46-3.93) Hz, P < 0.001; RI: 0.53 (0.48-0.56) vs. 0.63 (0.60-0.65), P < 0.001]. In a multivariate analysis controlled by the type of pathology and clinical variables, regularity remained an independent predictor of self-termination [hazard ratio: 0.954 (0.928-0.980)]. Receiver operating characteristic (ROC) curve analysis of DF and RI intensities demonstrated increased predictability for self-termination in time with 95% CI above the 0.5 cut-off limit at about t = 8.6 s and t = 6.95 s, respectively. CONCLUSION: Consistent with the notion that fast organized sources maintain PVT/VF in humans, reduction of frequency and regularity correlates with early self-termination. Our findings might help generate ICD methods aiming to reduce inappropriate shock deliveries.

Short-wave infrared light imaging measures tissue moisture and distinguishes superficial from deep burns.

Existing clinical approaches and tools to measure burn tissue destruction are limited resulting in misdiagnosis of injury depth in over 40% of cases. Thus, our objective in this study was to characterize the ability of short-wave infrared (SWIR) imaging to detect moisture levels as a surrogate for tissue viability with resolution to differentiate between burns of various depths. To accomplish our aim, we constructed an imaging system consisting of a broad-band Tungsten light source; 1,200-, 1,650-, 1,940-, and 2,250-nm wavelength filters; and a specialized SWIR camera. We initially used agar slabs to provide a baseline spectrum for SWIR light imaging and demonstrated the differential absorbance at the multiple wavelengths, with 1,940 nm being the highest absorbed wavelength. These spectral bands were then demonstrated to detect levels of moisture in inorganic and in vivo mice models. The multiwavelength SWIR imaging approach was used to diagnose depth of burns using an in vivo porcine burn model. Healthy and injured skin regions were imaged 72 hours after short (20 seconds) and long (60 seconds) burn application, and biopsies were extracted from those regions for histologic analysis. Burn depth analysis based on collagen coagulation histology confirmed the formation of superficial and deep burns. SWIR multispectral reflectance imaging showed enhanced intensity levels in long burned regions, which correlated with histology and distinguished between superficial and deep burns. This SWIR imaging method represents a novel, real-time method to objectively distinguishing superficial from deep burns.

Factors affecting basket catheter detection of real and phantom rotors in the atria: A computational study.

Anatomically based procedures to ablate atrial fibrillation (AF) are often successful in terminating paroxysmal AF. However, the ability to terminate persistent AF remains disappointing. New mechanistic approaches use multiple-electrode basket catheter mapping to localize and target AF drivers in the form of rotors but significant concerns remain about their accuracy. We aimed to evaluate how electrode-endocardium distance, far-field sources and inter-electrode distance affect the accuracy of localizing rotors. Sustained rotor activation of the atria was simulated numerically and mapped using a virtual basket catheter with varying electrode densities placed at different positions within the atrial cavity. Unipolar electrograms were calculated on the entire endocardial surface and at each of the electrodes. Rotors were tracked on the interpolated basket phase maps and compared with the respective atrial voltage and endocardial phase maps, which served as references. Rotor detection by the basket maps varied between 35-94% of the simulation time, depending on the basket's position and the electrode-to-endocardial wall distance. However, two different types of phantom rotors appeared also on the basket maps. The first type was due to the far-field sources and the second type was due to interpolation between the electrodes; increasing electrode density decreased the incidence of the second but not the first type of phantom rotors. In the simulations study, basket catheter-based phase mapping detected rotors even when the basket was not in full contact with the endocardial wall, but always generated a number of phantom rotors in the presence of only a single real rotor, which would be the desired ablation target. Phantom rotors may mislead and contribute to failure in AF ablation procedures.

Causality analysis of leading singular value decomposition modes identifies rotor as the dominant driving normal mode in fibrillation.

Cardiac fibrillation is a major clinical and societal burden. Rotors may drive fibrillation in many cases, but their role and patterns are often masked by complex propagation. We used Singular Value Decomposition (SVD), which ranks patterns of activation hierarchically, together with Wiener-Granger causality analysis (WGCA), which analyses direction of information among observations, to investigate the role of rotors in cardiac fibrillation. We hypothesized that combining SVD analysis with WGCA should reveal whether rotor activity is the dominant driving force of fibrillation even in cases of high complexity. Optical mapping experiments were conducted in neonatal rat cardiomyocyte monolayers (diameter, 35 mm), which were genetically modified to overexpress the delayed rectifier K+ channel IKr only in one half of the monolayer. Such monolayers have been shown previously to sustain fast rotors confined to the IKr overexpressing half and driving fibrillatory-like activity in the other half. SVD analysis of the optical mapping movies revealed a hierarchical pattern in which the primary modes corresponded to rotor activity in the IKr overexpressing region and the secondary modes corresponded to fibrillatory activity elsewhere. We then applied WGCA to evaluate the directionality of influence between modes in the entire monolayer using clear and noisy movies of activity. We demonstrated that the rotor modes influence the secondary fibrillatory modes, but influence was detected also in the opposite direction. To more specifically delineate the role of the rotor in fibrillation, we decomposed separately the respective SVD modes of the rotor and fibrillatory domains. In this case, WGCA yielded more information from the rotor to the fibrillatory domains than in the opposite direction. In conclusion, SVD analysis reveals that rotors can be the dominant modes of an experimental model of fibrillation. Wiener-Granger causality on modes of the rotor domains confirms their preferential driving influence on fibrillatory modes.

Noninvasive Estimation of Epicardial Dominant High-Frequency Regions During Atrial Fibrillation.

INTRODUCTION: Ablation of high dominant frequency (DF) sources in patients with atrial fibrillation (AF) is an effective treatment option for paroxysmal AF. The aim of this study was to evaluate the accuracy of noninvasive estimation of DF and electrical patterns determination by solving the inverse problem of the electrocardiography. METHODS: Four representative AF patients with left-to-right and right-to-left atrial DF patterns were included in the study. For each patient, intracardiac electrograms from both atria were recorded simultaneously together with 67-lead body surface recordings. In addition to clinical recordings, realistic mathematical models of atria and torso anatomy with different DF patterns of AF were used. For both mathematical models and clinical recordings, inverse-computed electrograms were compared to intracardiac electrograms in terms of voltage, phase, and frequency spectrum relative errors. RESULTS: Comparison between intracardiac and inverse computed electrograms for AF patients showed 8.8 ± 4.4% errors for DF, 32 ± 4% for voltage, and 65 ± 4% for phase determination. These results were corroborated by mathematical simulations showing that the inverse problem solution was able to reconstruct the frequency spectrum and the DF maps with relative errors of 5.5 ± 4.1%, whereas the reconstruction of the electrograms or the instantaneous phase presented larger relative errors (i.e., 38 ± 15% and 48 ± 14 % respectively, P < 0.01). CONCLUSIONS: Noninvasive reconstruction of atrial frequency maps can be achieved by solving the inverse problem of electrocardiography with a higher accuracy than temporal distribution patterns.

KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.

We describe a mutation (E299V) in KCNJ2, the gene that encodes the strong inward rectifier K(+) channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of KCNJ2 that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward IK1 at potentials above -55 mV (P < 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild-type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His-Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia.

Mechanisms of Atrial Fibrillation: Rotors, Ionic Determinants, and Excitation Frequency.

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.

Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation.

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 we tested the hypothesis that the rate of electric and 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 euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the 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 correlated strongly with the time to persistent AF. Significant action potential duration 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 1 year of follow up. CONCLUSIONS: In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.

Attraction of rotors to the pulmonary veins in paroxysmal atrial fibrillation: a modeling study.

Maintenance of paroxysmal atrial fibrillation (AF) by fast rotors in the left atrium (LA) or at the pulmonary veins (PVs) is not fully understood. To gain insight into this dynamic and complex process, we studied the role of the heterogeneous distribution of transmembrane currents in the PVs and LA junction (PV-LAJ) in the localization of rotors in the PVs. We also investigated whether simple pacing protocols could be used to predict rotor drift in the PV-LAJ. Experimentally observed heterogeneities in IK1, IKs, IKr, Ito, and ICaL in the PV-LAJ were incorporated into two- and pseudo three-dimensional models of Courtemanche-Ramirez-Nattel-Kneller human atrial kinetics to simulate various conditions and investigate rotor drifting mechanisms. Spatial gradients in the currents resulted in shorter action potential duration, minimum diastolic potential that was less negative, and slower upstroke and conduction velocity for rotors in the PV region than in the LA. Rotors under such conditions drifted toward the PV and stabilized at the shortest action potential duration and less-excitable region, consistent with drift direction under intercellular coupling heterogeneities and regardless of the geometrical constraint in the PVs. Simulations with various IK1 gradient conditions and current-voltage relationships substantiated its major role in the rotor drift. In our 1:1 pacing protocol, we found that among various action potential properties, only the minimum diastolic potential gradient was a rate-independent predictor of rotor drift direction. Consistent with experimental and clinical AF studies, simulations in an electrophysiologically heterogeneous model of the PV-LAJ showed rotor attraction toward the PV. Our simulations suggest that IK1 heterogeneity is dominant compared to other currents in determining the drift direction through its impact on the excitability gradient. These results provide a believed novel framework for understanding the complex dynamics of rotors in AF.

Genetic risk factors for drug-induced long QT syndrome: findings from a large real-world case-control study.

Aim: Drug-induced long QT syndrome (diLQTS), an adverse effect of many drugs, can lead to sudden cardiac death. Candidate genetic variants in cardiac ion channels have been associated with diLQTS, but several limitations of previous studies hamper clinical utility. Materials & methods: Thus, the purpose of this study was to assess the associations of KCNE1-D85N, KCNE2-I57T and SCN5A-G615E with diLQTS in a large observational case-control study (6,083 self-reported white patients treated with 27 different high-risk QT-prolonging medications; 12.0% with diLQTS). Results: KCNE1-D85N significantly associated with diLQTS (adjusted odds ratio: 2.24 [95% CI: 1.35-3.58]; p = 0.001). Given low minor allele frequencies, the study had insufficient power to analyze KCNE2-I57T and SCN5A-G615E. Conclusion: KCNE1-D85N is a risk factor for diLQTS that should be considered in future clinical practice guidelines.

Some medications can lead to a condition called drug-induced long QT syndrome (diLQTS), which can be a serious abnormal heart rhythm in some patients. In our research, we explored three specific changes in DNA related to the electrical function of the heart (KCNE1-D85N, KCNE2-I57T, SCN5A-G615E) and their link to diLQTS. Our study revealed a connection between KCNE1-D85N and diLQTS. This study emphasized the importance of including KCNE1-D85N in the medical guidelines to help identify patients at risk of diLQTS. We were unable to identify the connection of KCNE2-I57T and SCN5A-G615E with diLQTS, due to a low number of carriers in the study.

ELUCIDATING THE ROLE OF THE HIS-PURKINJE SYSTEM DURING LONG QT MEDIATED ARRHYTHMIAS.

Mutation in the hERG gene leading to partial or complete blockade of the rapid delayed rectifier current causes Long QT Type 2 (LQT2) phenotype, the second most common form of Long QT Syndrome. However, the exact involvement of the His-Purkinje System (HPS) remains elusive. We utilized a finite element model of the rabbit ventricles integrated with a HPS to elucidate the role of HPS during LQT2-mediated arrhythmia. Following the induction of persistent reentry from an ectopic stimulus, we isolated the HPS at different time points. Moreover, we varied the coupling resistance and the number of myocytes at the Purkinje-Myocardial Junctions (PMJs) to ascertain how the junctional parameters altered reentry dynamics. Reentry was terminated with the earliest termination time for reentry coinciding with the earliest time the HPS was isolated. This observation provides evidence of direct involvement of the HPS during LQT2-mediated ventricular arrhythmia. Increasing the coupling resistance or the number of myocytes at the PMJs reduced the percentage of successful retrograde propagation during reentry. Thus, the HPS alters reentry dynamics. Our multi-scale computer modeling outcomes offer important new understandings of probable arrhythmia mechanisms under LQT2 circumstances.

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

Spatial dispersion of action potential duration (APD) is a substrate for the maintenance of cardiac fibrillation, but the mechanisms are poorly understood. We investigated the role played by spatial APD dispersion in fibrillatory dynamics. We used an in vitro model in which spatial gradients in the expression of ether-à-go-go-related (hERG) protein, and thus rapid delayed rectifying K(+) current (I(Kr)) density, served to generate APD dispersion, high-frequency rotor formation, wavebreak and fibrillatory conduction. A unique adenovirus-mediated magnetofection technique generated well-controlled gradients in hERG and green fluorescent protein (GFP) expression in neonatal rat ventricular myocyte monolayers. Computer simulations using a realistic neonatal rat ventricular myocyte monolayer model provided crucial insight into the underlying mechanisms. Regional hERG overexpression shortened APD and increased rotor incidence in the hERG overexpressing region. An APD profile at 75 percent repolarization with a 16.6 ± 0.72 ms gradient followed the spatial profile of hERG-GFP expression; conduction velocity was not altered. Rotors in the infected region whose maximal dominant frequency was 12.9 Hz resulted in wavebreak at the interface (border zone) between infected and non-infected regions; dominant frequency distribution was uniform when the maximal dominant frequency was <12.9 Hz or the rotors resided in the uninfected region. Regularity at the border zone was lowest when rotors resided in the infected region. In simulations, a fivefold regional increase in I(Kr) abbreviated the APD and hyperpolarized the resting potential. However, the steep APD gradient at the border zone proved to be the primary mechanism of wavebreak and fibrillatory conduction. This study provides insight at the molecular level into the mechanisms by which spatial APD dispersion contributes to wavebreak, rotor stabilization and fibrillatory conduction.

A major role for HERG in determining frequency of reentry in neonatal rat ventricular myocyte monolayer.

RATIONALE: the rapid delayed rectifier potassium current, I(Kr), which flows through the human ether-a-go-go-related (hERG) channel, is a major determinant of the shape and duration of the human cardiac action potential (APD). However, it is unknown whether the time dependency of I(Kr) enables it to control APD, conduction velocity (CV), and wavelength (WL) at the exceedingly high activation frequencies that are relevant to cardiac reentry and fibrillation. OBJECTIVE: to test the hypothesis that upregulation of hERG increases functional reentry frequency and contributes to its stability. METHODS AND RESULTS: using optical mapping, we investigated the effects of I(Kr) upregulation on reentry frequency, APD, CV, and WL in neonatal rat ventricular myocyte (NRVM) monolayers infected with GFP (control), hERG (I(Kr)), or dominant negative mutant hERG G628S. Reentry frequency was higher in the I(Kr)-infected monolayers (21.12 ± 0.8 Hz; n=43 versus 9.21 ± 0.58 Hz; n=16; P<0.001) but slightly reduced in G628S-infected monolayers. APD(80) in the I(Kr)-infected monolayers was shorter (>50%) than control during pacing at 1 to 5 Hz. CV was similar in both groups at low frequency pacing. In contrast, during high-frequency reentry, the CV measured at varying distances from the center of rotation was significantly faster in I(Kr)-infected monolayers than controls. Simulations using a modified NRVM model predicted that rotor acceleration was attributable, in part, to a transient hyperpolarization immediately following the AP. The transient hyperpolarization was confirmed experimentally. CONCLUSIONS: hERG overexpression dramatically accelerates reentry frequency in NRVM monolayers. Both APD and WL shortening, together with transient hyperpolarization, underlies the increased rotor frequency and stability.

High-rate pacing-induced atrial fibrillation effectively reveals properties of spontaneously occurring paroxysmal atrial fibrillation in humans.

AIMS: Research on paroxysmal atrial fibrillation (AF) assumes that fibrillation induced by rapid pacing adequately reproduces spontaneously occurring paroxysmal AF in humans. We aimed to compare the spectral properties of spontaneous vs. induced AF episodes in paroxysmal AF patients. METHODS AND RESULTS: Eighty-five paroxysmal AF patients arriving in sinus rhythm to the electrophysiology laboratory were evaluated prior to ablation. Atrial fibrillation was induced by rapid pacing from the pulmonary vein-left atrial junctions (PV-LAJ), the coronary sinus (CS), or the high right atrium (HRA). Simultaneous recordings were obtained using multipolar catheters. Off-line power spectral analysis of 5 s bipolar electrograms was used to determine dominant frequency (DF) at recording sites with regularity index >0.2. Sixty-eight episodes were analysed for DF. Comparisons were made between spontaneous (n = 23) and induced (n = 45) AF episodes at each recording site. No significant differences were observed between spontaneous and induced AF episodes in HRA (5.18 ± 0.69 vs. 5.06 ± 0.91 Hz; P = 0.64), CS (5.27 ± 0.69 vs. 5.36 ± 0.76 Hz; P = 0.69), or LA (5.72 ± 0.88 vs. 5.64 ± 0.75 Hz; P = 0.7) regardless of pacing site. Consistent with these results, paired analysis in seven patients with both spontaneous and induced AF episodes, showed no regional DFs differences. Moreover, a left-to-right DF gradient was also present in both spontaneous (PV-LAJ 5.71 ± 0.81 vs. HRA 5.18 ± 0.69 Hz; P = 0.005) and induced (PV-LAJ 5.62 ± 0.72 vs. HRA 5.07 ± 0.91 Hz; P = 0.002) AF episodes, with no differences between them (P = not specific). CONCLUSION: In patients with paroxysmal AF, high-rate pacing-induced AF adequately mimics spontaneously initiated AF, regardless of induction site.

Rotors Drift Toward and Stabilize in Low Power Regions in Heterogeneous Models of Atrial Fibrillation.

Atrial fibrillation (AF) afflicts more than 33 million people worldwide. Success of therapy strategies remains poor and better understanding of the arrhythmia and how to device more effective therapies are needed. The aim of this work is to study the role of electric power distributions in rotors and AF dynamics. For this purpose, single cell and tissue simulations were performed to study the effect of ionic currents gradients and fibrosis in rotor's drifting. The root mean square of the ionic (Pion), capacitance (Pc) and electrotonic (Pele) power was computed over action potentials. Single cell simulations were performed for different values of IK1 and ICaL and number of coupled myofibroblasts. Tissue simulations were performed in presence of IK1 and ICaL gradients and diffused fibrosis. Single cell simulations showed that Pion and Pc increased with IK1, while decreased by increasing ICaL. Increasing the number of coupled myofibroblasts reduced Pion and Pc, whereas Pele increased. Finally, in tissue simulations rotors drifted to regions with low power and anchored in regions with higher density of blunted ionic induced power gradients.

TIME- AND FREQUENCY-BASED INDEPENDENT EVALUATION OF QRST CANCELLATION TECHNIQUES FOR SINGLE-LEAD ELECTROCARDIOGRAMS DURING ATRIAL FIBRILLATION.

With the increased prevalence of atrial fibrillation (AF) - a rhythm disturbance in heart's top chambers - there is growing interest in accurate non-invasive diagnosis of atrial activity to improve its therapy. A key component in non-invasive analysis of atrial activity is a successful removal of the ventricular QRST complexes from electrocardiograms (ECGs). In this study, we have developed a new approach for an objective and physiologically-based evaluation of QRST cancellation methods based on comparisons with the power spectra of the AF. Three commonly used QRST cancellation methods were evaluated; namely, average beat subtraction, singular value cancellation, and principal component analysis. These methods were evaluated in time and frequency domains using a set of synthesized ECGs preserving the atrial-specific temporal and spectral properties. It was observed that the ABS method provided the best estimation when QRST morphological variability is low, while PCA produces an overall best estimate when a large QRST morphological variability is present.

Artificial intelligence analysis of the impact of fibrosis in arrhythmogenesis and drug response.

Background: Cardiac fibrosis has been identified as a major factor in conduction alterations leading to atrial arrhythmias and modification of drug treatment response. Objective: To perform an in silico proof-of-concept study of Artificial Intelligence (AI) ability to identify susceptibility for conduction blocks in simulations on a population of models with diffused fibrotic atrial tissue and anti-arrhythmic drugs. Methods: Activity in 2D cardiac tissue planes were simulated on a population of variable electrophysiological and anatomical profiles using the Koivumaki model for the atrial cardiomyocytes and the Maleckar model for the diffused fibroblasts (0%, 5% and 10% fibrosis area). Tissue sheets were of 2 cm side and the effect of amiodarone, dofetilide and sotalol was simulated to assess the conduction of the electrical impulse across the planes. Four different AI algorithms (Quadratic Support Vector Machine, QSVM, Cubic Support Vector Machine, CSVM, decision trees, DT, and K-Nearest Neighbors, KNN) were evaluated in predicting conduction of a stimulated electrical impulse. Results: Overall, fibrosis implementation lowered conduction velocity (CV) for the conducting profiles (0% fibrosis: 67.52 ± 7.3 cm/s; 5%: 58.81 ± 14.04 cm/s; 10%: 57.56 ± 14.78 cm/s; p < 0.001) in combination with a reduced 90% action potential duration (0% fibrosis: 187.77 ± 37.62 ms; 5%: 93.29 ± 82.69 ms; 10%: 106.37 ± 85.15 ms; p < 0.001) and peak membrane potential (0% fibrosis: 89.16 ± 16.01 mV; 5%: 70.06 ± 17.08 mV; 10%: 82.21 ± 19.90 mV; p < 0.001). When the antiarrhythmic drugs were present, a total block was observed in most of the profiles. In those profiles in which electrical conduction was preserved, a decrease in CV was observed when simulations were performed in the 0% fibrosis tissue patch (Amiodarone ΔCV: -3.59 ± 1.52 cm/s; Dofetilide ΔCV: -13.43 ± 4.07 cm/s; Sotalol ΔCV: -0.023 ± 0.24 cm/s). This effect was preserved for amiodarone in the 5% fibrosis patch (Amiodarone ΔCV: -4.96 ± 2.15 cm/s; Dofetilide ΔCV: 0.14 ± 1.87 cm/s; Sotalol ΔCV: 0.30 ± 4.69 cm/s). 10% fibrosis simulations showed that part of the profiles increased CV while others showed a decrease in this variable (Amiodarone ΔCV: 0.62 ± 9.56 cm/s; Dofetilide ΔCV: 0.05 ± 1.16 cm/s; Sotalol ΔCV: 0.22 ± 1.39 cm/s). Finally, when the AI algorithms were tested for predicting conduction on input of variables from the population of modelled, Cubic SVM showed the best performance with AUC = 0.95. Conclusion: In silico proof-of-concept study demonstrates that fibrosis can alter the expected behavior of antiarrhythmic drugs in a minority of atrial population models and AI can assist in revealing the profiles that will respond differently.

Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets.

Atrial and ventricular tachyarrhythmias can be perpetuated by up-regulation of inward rectifier potassium channels. Thus, it may be beneficial to block inward rectifier channels under conditions in which their function becomes arrhythmogenic (e.g., inherited gain-of-function mutation channelopathies, ischemia, and chronic and vagally mediated atrial fibrillation). We hypothesize that the antimalarial quinoline chloroquine exerts potent antiarrhythmic effects by interacting with the cytoplasmic domains of Kir2.1 (I(K1)), Kir3.1 (I(KACh)), or Kir6.2 (I(KATP)) and reducing inward rectifier potassium currents. In isolated hearts of three different mammalian species, intracoronary chloroquine perfusion reduced fibrillatory frequency (atrial or ventricular), and effectively terminated the arrhythmia with resumption of sinus rhythm. In patch-clamp experiments chloroquine blocked I(K1), I(KACh), and I(KATP). Comparative molecular modeling and ligand docking of chloroquine in the intracellular domains of Kir2.1, Kir3.1, and Kir6.2 suggested that chloroquine blocks or reduces potassium flow by interacting with negatively charged amino acids facing the ion permeation vestibule of the channel in question. These results open a novel path toward discovering antiarrhythmic pharmacophores that target specific residues of the cytoplasmic domain of inward rectifier potassium channels.

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.

Electrocardiographic Imaging for Atrial Fibrillation: A Perspective From Computer Models and Animal Experiments to Clinical Value.

Electrocardiographic imaging (ECGI) is a technique to reconstruct non-invasively the electrical activity on the heart surface from body-surface potential recordings and geometric information of the torso and the heart. ECGI has shown scientific and clinical value when used to characterize and treat both atrial and ventricular arrhythmias. Regarding atrial fibrillation (AF), the characterization of the electrical propagation and the underlying substrate favoring AF is inherently more challenging than for ventricular arrhythmias, due to the progressive and heterogeneous nature of the disease and its manifestation, the small volume and wall thickness of the atria, and the relatively large role of microstructural abnormalities in AF. At the same time, ECGI has the advantage over other mapping technologies of allowing a global characterization of atrial electrical activity at every atrial beat and non-invasively. However, since ECGI is time-consuming and costly and the use of electrical mapping to guide AF ablation is still not fully established, the clinical value of ECGI for AF is still under assessment. Nonetheless, AF is known to be the manifestation of a complex interaction between electrical and structural abnormalities and therefore, true electro-anatomical-structural imaging may elucidate important key factors of AF development, progression, and treatment. Therefore, it is paramount to identify which clinical questions could be successfully addressed by ECGI when it comes to AF characterization and treatment, and which questions may be beyond its technical limitations. In this manuscript we review the questions that researchers have tried to address on the use of ECGI for AF characterization and treatment guidance (for example, localization of AF triggers and sustaining mechanisms), and we discuss the technological requirements and validation. We address experimental and clinical results, limitations, and future challenges for fruitful application of ECGI for AF understanding and management. We pay attention to existing techniques and clinical application, to computer models and (animal or human) experiments, to challenges of methodological and clinical validation. The overall objective of the study is to provide a consensus on valuable directions that ECGI research may take to provide future improvements in AF characterization and treatment guidance.