Regional conduction velocities determined by noninvasive mapping are associated with arrhythmia-free survival after atrial fibrillation ablation.

BACKGROUND: Atrial arrhythmogenic substrate is a key determinant of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI), and reduced conduction velocities have been linked to adverse outcome. However, a noninvasive method to assess such electrophysiologic substrate is not available to date. OBJECTIVE: This study aimed to noninvasively assess regional conduction velocities and their association with arrhythmia-free survival after PVI. METHODS: A consecutive 52 patients scheduled for AF ablation (PVI only) and 19 healthy controls were prospectively included and received electrocardiographic imaging (ECGi) to noninvasively determine regional atrial conduction velocities in sinus rhythm. A novel ECGi technology obviating the need of additional computed tomography or cardiac magnetic resonance imaging was applied and validated by invasive mapping. RESULTS: Mean ECGi-determined atrial conduction velocities were significantly lower in AF patients than in healthy controls (1.45 ± 0.15 m/s vs 1.64 ± 0.15 m/s; P < .0001). Differences were particularly pronounced in a regional analysis considering only the segment with the lowest average conduction velocity in each patient (0.8 ± 0.22 m/s vs 1.08 ± 0.26 m/s; P < .0001). This average conduction velocity of the "slowest" segment was independently associated with arrhythmia recurrence and better discriminated between PVI responders and nonresponders than previously proposed predictors, including left atrial size and late gadolinium enhancement (magnetic resonance imaging). Patients without slow-conduction areas (mean conduction velocity <0.78 m/s) showed significantly higher 12-month arrhythmia-free survival than those with 1 or more slow-conduction areas (88.9% vs 48.0%; P = .002). CONCLUSION: This is the first study to investigate regional atrial conduction velocities noninvasively. The absence of ECGi-determined slow-conduction areas well discriminates PVI responders from nonresponders. Such noninvasive assessment of electrical arrhythmogenic substrate may guide treatment strategies and be a step toward personalized AF therapy.

Non-invasive estimation of atrial fibrillation driver position using long-short term memory neural networks and body surface potentials.

BACKGROUND AND OBJECTIVE: Atrial Fibrillation (AF) is a supraventricular tachyarrhythmia that can lead to thromboembolism, hearlt failure, ischemic stroke, and a decreased quality of life. Characterizing the locations where the mechanisms of AF are initialized and maintained is key to accomplishing an effective ablation of the targets, hence restoring sinus rhythm. Many methods have been investigated to locate such targets in a non-invasive way, such as Electrocardiographic Imaging, which enables an on-invasive and panoramic characterization of cardiac electrical activity using recording Body Surface Potentials (BSP) and a torso model of the patient. Nonetheless, this technique entails some major issues stemming from solving the inverse problem, which is known to be severely ill-posed. In this context, many machine learning and deep learning approaches aim to tackle the characterization and classification of AF targets to improve AF diagnosis and treatment. METHODS: In this work, we propose a method to locate AF drivers as a supervised classification problem. We employed a hybrid form of the convolutional-recurrent network which enables feature extraction and sequential data modeling utilizing labeled realistic computerized AF models. Thus, we used 16 AF electrograms, 1 atrium, and 10 torso geometries to compute the forward problem. Previously, the AF models were labeled by assigning each sample of the signals a region from the atria from 0 (no driver) to 7, according to the spatial location of the AF driver. The resulting 160 BSP signals, which resemble a 64-lead vest recording, are preprocessed and then introduced into the network following a 4-fold cross-validation in batches of 50 samples. RESULTS: The results show a mean accuracy of 74.75% among the 4 folds, with a better performance in detecting sinus rhythm, and drivers near the left superior pulmonary vein (R1), and right superior pulmonary vein (R3) whose mean sensitivity bounds around 84%-87%. Significantly good results are obtained in mean sensitivity (87%) and specificity (83%) in R1. CONCLUSIONS: Good results in R1 are highly convenient since AF drivers are commonly found in this area: the left atrial appendage, as suggested in some previous studies. These promising results indicate that using CNN-LSTM networks could lead to new strategies exploiting temporal correlations to address this challenge effectively.

Modeling Cardiotoxicity in Pediatric Oncology Patients Using Patient-Specific iPSC-Derived Cardiomyocytes Reveals Downregulation of Cardioprotective microRNAs.

Anthracyclines are widely used in the treatment of many solid cancers, but their efficacy is limited by cardiotoxicity. As the number of pediatric cancer survivors continues to rise, there has been a concomitant increase in people living with anthracycline-induced cardiotoxicity. Accordingly, there is an ongoing need for new models to better understand the pathophysiological mechanisms of anthracycline-induced cardiac damage. Here we generated induced pluripotent stem cells (iPSCs) from two pediatric oncology patients with acute cardiotoxicity induced by anthracyclines and differentiated them to ventricular cardiomyocytes (hiPSC-CMs). Comparative analysis of these cells (CTX hiPSC-CMs) and control hiPSC-CMs revealed that the former were significantly more sensitive to cell injury and death from the anthracycline doxorubicin (DOX), as measured by viability analysis, cleaved caspase 3 expression, oxidative stress, genomic and mitochondrial damage and sarcomeric disorganization. The expression of several mRNAs involved in structural integrity and inflammatory response were also differentially affected by DOX. Functionally, optical mapping analysis revealed higher arrythmia complexity after DOX treatment in CTX iPSC-CMs. Finally, using a panel of previously identified microRNAs associated with cardioprotection, we identified lower levels of miR-22-3p, miR-30b-5p, miR-90b-3p and miR-4732-3p in CTX iPSC-CMs under basal conditions. Our study provides valuable phenotype information for cellular models of cardiotoxicity and highlights the significance of using patient-derived cardiomyocytes for studying the associated pathogenic mechanisms.

AF driver detection in pulmonary vein area by electropcardiographic imaging: Relation with a favorable outcome of pulmonary vein isolation.

Pulmonary vein isolation (PVI) is the most successful treatment for atrial fibrillation (AF) nowadays. However, not all AF patients benefit from PVI. In this study, we evaluate the use of ECGI to identify reentries and relate rotor density in the pulmonary vein (PV) area as an indicator of PVI outcome. Rotor maps were computed in a set of 29 AF patients using a new rotor detection algorithm. The relationship between the distribution of reentrant activity and the clinical outcome after PVI was studied. The number of rotors and proportion of PSs in different atrial regions were computed and compared retrospectively in two groups of patients: patients that remained in sinus rhythm 6 months after PVI and patients with arrhythmia recurrence. The total number of rotors obtained was higher in patients returning to arrhythmia after the ablation (4.31 ± 2.77 vs. 3.58 ± 2.67%, p = 0.018). However, a significantly higher concentration of PSs in the pulmonary veins was found in patients that remained in sinus rhythm (10.20 ± 12.40% vs. 5.19 ± 9.13%, p = 0.011) 6 months after PVI. The results obtained show a direct relationship between the expected AF mechanism and the electrophysiological parameters provided by ECGI, suggesting that this technology offers relevant information to predict the clinical outcome after PVI in AF patients.

Robustness of imageless electrocardiographic imaging against uncertainty in atrial morphology and location.

INTRODUCTION: Electrocardiographic Imaging is a non-invasive technique that requires cardiac Imaging for the reconstruction of cardiac electrical activity. In this study, we explored imageless ECGI by quantifying the errors of using heart meshes with either an inaccurate location inside the thorax or an inaccurate geometry. METHODS: Multiple­lead body surface recordings of 25 atrial fibrillation (AF) patients were recorded. Cardiac atrial meshes were obtained by segmentation of medical images obtained for each patient. ECGI was computed with each patient's segmented atrial mesh and compared with the ECGI obtained under errors in the atrial mesh used for ECGI estimation. We modeled both the uncertainty in the location of the atria inside the thorax by artificially translating the atria inside the thorax and the geometry of the atrial mesh by using an atrial mesh in a reference database. ECGI signals obtained with the actual meshes and the translated or estimated meshes were compared in terms of their correlation coefficients, relative difference measurement star, and errors in the dominant frequency (DF) estimation in epicardial nodes. RESULTS: CC between ECGI signals obtained after translating the actual atrial meshes from the original position by 1 cm was above 0.97. CC between ECGIs obtained with patient specific atrial geometry and estimated atrial geometries was 0.93 ± 0.11. Mean errors in DF estimation using an estimated atrial mesh were 7.6 ± 5.9%. CONCLUSION: Imageless ECGI can provide a robust estimation of cardiac electrophysiological parameters such as activation rates even during complex arrhythmias. Furthermore, it can allow more widespread use of ECGI in clinical practice.

Electrocardiographic imaging in the atria.

The inverse problem of electrocardiography or electrocardiographic imaging (ECGI) is a technique for reconstructing electrical information about cardiac surfaces from noninvasive or non-contact recordings. ECGI has been used to characterize atrial and ventricular arrhythmias. Although it is a technology with years of progress, its development to characterize atrial arrhythmias is challenging. Complications can arise when trying to describe the atrial mechanisms that lead to abnormal propagation patterns, premature or tachycardic beats, and reentrant arrhythmias. This review addresses the various ECGI methodologies, regularization methods, and post-processing techniques used in the atria, as well as the context in which they are used. The current advantages and limitations of ECGI in the fields of research and clinical diagnosis of atrial arrhythmias are outlined. In addition, areas where ECGI efforts should be concentrated to address the associated unsatisfied needs from the atrial perspective are discussed.

Effects of torso mesh density and electrode distribution on the accuracy of electrocardiographic imaging during atrial fibrillation.

Introduction: Electrocardiographic Imaging (ECGI) allows computing the electrical activity in the heart non-invasively using geometrical information of the patient and multiple body surface signals. In the present study we investigate the influence of the number of nodes of geometrical meshes and recording ECG electrodes distribution to compute ECGI during atrial fibrillation (AF). Methods: Torso meshes from 100 to 2000 nodes heterogeneously and homogeneously distributed were compared. Signals from nine AF realistic mathematical simulations were used for computing the ECGI. Results for each torso mesh were compared with the ECGI computed with a 4,000 nodes reference torso. In addition, real AF recordings from 25 AF patients were used to compute ECGI in torso meshes from 100 to 1,000 nodes. Results were compared with a reference torso of 2000 nodes. Torsos were remeshed either by reducing the number of nodes while maximizing the overall shape preservation and then assigning the location of the electrodes as the closest node in the new mesh or by forcing the remesher to place a node at each electrode location. Correlation coefficients, relative difference measurements and relative difference of dominant frequencies were computed to evaluate the impact on signal morphology of each torso mesh. Results: For remeshed torsos where electrodes match with a geometrical node in the mesh, all mesh densities presented similar results. On the other hand, in torsos with electrodes assigned to closest nodes in remeshed geometries performance metrics were dependent on mesh densities, with correlation coefficients ranging from 0.53 ± 0.06 to 0.92 ± 0.04 in simulations or from 0.42 ± 0.38 to 0.89 ± 0.2 in patients. Dominant frequency relative errors showed the same trend with values from 1.14 ± 0.26 to 0.55 ± 0.21 Hz in simulations and from 0.91 ± 0.56 to 0.45 ± 0.41 Hz in patients. Conclusion: The effect of mesh density in ECGI is minimal when the location of the electrode is preserved as a node in the mesh. Torso meshes constructed without imposing electrodes to constitute nodes in the torso geometry should contain at least 400 nodes homogeneously distributed so that a distance between nodes is below 4 cm.

Non-invasive Estimation of Atrial Fibrillation Driver Position With Convolutional Neural Networks and Body Surface Potentials.

Atrial fibrillation (AF) is characterized by complex and irregular propagation patterns, and AF onset locations and drivers responsible for its perpetuation are the main targets for ablation procedures. ECG imaging (ECGI) has been demonstrated as a promising tool to identify AF drivers and guide ablation procedures, being able to reconstruct the electrophysiological activity on the heart surface by using a non-invasive recording of body surface potentials (BSP). However, the inverse problem of ECGI is ill-posed, and it requires accurate mathematical modeling of both atria and torso, mainly from CT or MR images. Several deep learning-based methods have been proposed to detect AF, but most of the AF-based studies do not include the estimation of ablation targets. In this study, we propose to model the location of AF drivers from BSP as a supervised classification problem using convolutional neural networks (CNN). Accuracy in the test set ranged between 0.75 (SNR = 5 dB) and 0.93 (SNR = 20 dB upward) when assuming time independence, but it worsened to 0.52 or lower when dividing AF models into blocks. Therefore, CNN could be a robust method that could help to non-invasively identify target regions for ablation in AF by using body surface potential mapping, avoiding the use of ECGI.

Analysis of the response of human iPSC-derived cardiomyocyte tissue to ICaL block. A combined in vitro and in silico approach.

The high incidence of cardiac arrythmias underlines the need for the assessment of pharmacological therapies. In this field of drug efficacy, as in the field of drug safety highlighted by the Comprehensive in Vitro Proarrhythmia Assay initiative, new pillars for research have become crucial: firstly, the integration of in-silico experiments, and secondly the evaluation of fully integrated biological systems, such as human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). In this study, we therefore aimed to combine in-vitro experiments and in-silico simulations to evaluate the antiarrhythmic effect of L-type calcium current (ICaL) block in hiPSC-CMs. For this, hiPSC-CM preparations were cultured and an equivalent virtual tissue was modeled. Re-entry patterns of electrical activation were induced and several biomarkers were obtained before and after ICaL block. The virtual hiPSC-CM simulations were also reproduced using a tissue composed of adult ventricular cardiomyocytes (hAdultV-CMs). The analysis of phases, currents and safety factor for propagation showed an increased size of the re-entry core when ICaL was blocked as a result of depressed cellular excitability. The bigger wavefront curvature yielded reductions of 12.2%, 6.9%, and 4.2% in the frequency of the re-entry for hiPSC-CM cultures, virtual hiPSC-CM, and hAdultV-CM tissues, respectively. Furthermore, ICaL block led to a 47.8% shortening of the vulnerable window for re-entry in the virtual hiPSC-CM tissue and to re-entry vanishment in hAdultV-CM tissue. The consistent behavior between in-vitro and in-silico hiPSC-CMs and between in-silico hiPSC-CMs and hAdultV-CMs evidences that virtual hiPSC-CM tissues are suitable for assessing cardiac efficacy, as done in the present study through the analysis of ICaL block.

#CienciaenelParlamento: la necesidad de una oficina parlamentaria de asesoramiento científico y tecnológico / #CienciaenelParlamento: the need for a parliamentary office of science and technology advice

Uno de los objetivos de la iniciativa ciudadana #CienciaenelParlamento es contribuir al establecimiento de una oficina parlamentaria de asesoramiento científico y tecnológico en las Cortes Generales. Dicha oficina estaría encargada de favorecer espacios de confluencia entre el conocimiento científico y las políticas públicas, y fomentar el debate entre políticos, expertos y la sociedad en general. En este artículo se revisan los principales mecanismos parlamentarios de asesoramiento científico, con especial atención a uno de ellos: las oficinas parlamentarias de asesoramiento científico y tecnológico. Estas oficinas existen en 22 parlamentos en todo el mundo, pero en España no. En segundo lugar, se describe la acción realizada por #CienciaenelParlamento en su colaboración con el Congreso de los Diputados durante la XII Legislatura, que culminó con unas jornadas en noviembre de 2018 en las que más de 200 científicos y casi 100 diputados debatieron sobre 12 temas de actualidad con el conocimiento científico más actualizado. Gracias a esta colaboración, el Congreso ha dado los primeros pasos para el establecimiento oficial de una oficina de asesoramiento científico. Por último, se exponen algunos ejemplos de cómo la acción de estas oficinas parlamentarias de asesoramiento científico y tecnológico en otros países se imbrica con la de otros agentes para un mayor debate público y la tramitación de mejores políticas públicas en temas de salud y otras áreas. Como conclusión, desde #CienciaenelParlamento creemos que una oficina asesora ayudaría a enriquecer el ecosistema ciencia-política en España. (AU)

One of the aims of the citizen's initiative #CienciaenelParlamento is helping to establishing a parliamentary office of scientific and technological advice in the Spanish parliament. Said office would be in charge of fostering networking spaces between scientific knowledge and public policies and of triggering public debate between policy-makers, experts and the general public. In this article, we first review the main parliamentary mechanisms of scientific advice, with special attention to one in particular: parliamentary offices of scientific and technological advice. These offices exist in 22 parliaments worldwide, but there are none in Spain. Second, we describe the activity undertaken by #CienciaenelParlamento in its collaboration with the Congress of Deputies during the 12th Spanish Legislature. This collaboration reached its peak with a two-day networking event in November 2018 with over 200 scientists and almost 100 deputies, who all debated twelve topics of social interest and the most up-to-date scientific knowledge. Thanks to this collaboration, the Congress has taken the first steps towards officially establishing a parliamentary science advice office. Lastly, we enumerate some examples about how these parliamentary offices in other countries have contributed with other stakeholders to better public debate and processing of public policies in public health and other areas. To conclude, we at #CienciaenelParlamento believe that a parliamentary science advice office would help to enhance the science-policy ecosystem in Spain. (AU)

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.

Reparative cell therapy for the heart: critical internal appraisal of the field in response to recent controversies.

The concept that cell-based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients.

Optimized single-point left ventricular pacing leads to improved resynchronization compared with multipoint pacing.

BACKGROUND: Multipoint pacing (MPP) in cardiac resynchronization therapy (CRT) activates the left ventricle from two locations, thereby shortening the QRS duration and enabling better resynchronization; however, compared with conventional CRT, MPP reduces battery longevity. On the other hand, electrocardiogram-based optimization using the fusion-optimized intervals (FOI) method achieves more significant reverse remodeling than nominal CRT programming. Our study aimed to determine whether MPP could attain better resynchronization than single-point pacing (SPP) optimized by FOI. METHODS: This prospective study included 32 consecutive patients who successfully received CRT devices with MPP capabilities. After implantation, the QRS duration was measured during intrinsic rhythm and with three pacing configurations: MPP, SPP-FOI, and MPP-FOI. In 14 patients, biventricular activation times (by electrocardiographic imaging, ECGI) were obtained during intrinsic rhythm and for each pacing configuration to validate the findings. Device battery longevity was estimated at the 45-day follow-up. RESULTS: The SPP-FOI method achieved greater QRS shortening than MPP (-56 ± 16 vs. -42 ± 17 ms, p < .001). Adding MPP to the best FOI programming did not result in further shortening (MPP-FOI: -58 ± 14 ms, p = .69). Although biventricular activation times did not differ significantly among the three pacing configurations, only the two FOI configurations achieved significant shortening compared with intrinsic rhythm. The estimated battery longevity was longer with SPP than with MPP (8.1 ± 2.3 vs. 6.3 ± 2.0 years, p = .03). CONCLUSIONS: SPP optimized by FOI resulted in better resynchronization and longer battery duration than MPP.

[#CienciaenelParlamento: the need for a parliamentary office of science and technology advice]. / #CienciaenelParlamento: la necesidad de una oficina parlamentaria de asesoramiento científico y tecnológico.

One of the aims of the citizen's initiative #CienciaenelParlamento is helping to establishing a parliamentary office of scientific and technological advice in the Spanish parliament. Said office would be in charge of fostering networking spaces between scientific knowledge and public policies and of triggering public debate between policy-makers, experts and the general public. In this article, we first review the main parliamentary mechanisms of scientific advice, with special attention to one in particular: parliamentary offices of scientific and technological advice. These offices exist in 22 parliaments worldwide, but there are none in Spain. Second, we describe the activity undertaken by #CienciaenelParlamento in its collaboration with the Congress of Deputies during the 12th Spanish Legislature. This collaboration reached its peak with a two-day networking event in November 2018 with over 200 scientists and almost 100 deputies, who all debated twelve topics of social interest and the most up-to-date scientific knowledge. Thanks to this collaboration, the Congress has taken the first steps towards officially establishing a parliamentary science advice office. Lastly, we enumerate some examples about how these parliamentary offices in other countries have contributed with other stakeholders to better public debate and processing of public policies in public health and other areas. To conclude, we at #CienciaenelParlamento believe that a parliamentary science advice office would help to enhance the science-policy ecosystem in Spain.

Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers.

BACKGROUND: Mechanical stretch increases Na+ inflow into myocytes, related to mechanisms including stretch-activated channels or Na+/H+ exchanger activation, involving Ca2+ increase that leads to changes in electrophysiological properties favoring arrhythmia induction. Ranolazine is an antianginal drug with confirmed beneficial effects against cardiac arrhythmias associated with the augmentation of I NaL current and Ca2+ overload. OBJECTIVE: This study investigates the effects of mechanical stretch on activation patterns in atrial cell monolayers and its pharmacological response to ranolazine. METHODS: Confluent HL-1 cells were cultured in silicone membrane plates and were stretched to 110% of original length. The characteristics of in vitro fibrillation (dominant frequency, regularity index, density of phase singularities, rotor meandering, and rotor curvature) were analyzed using optical mapping in order to study the mechanoelectric response to stretch under control conditions and ranolazine action. RESULTS: HL-1 cell stretch increased fibrillatory dominant frequency (3.65 ± 0.69 vs. 4.35 ± 0.74 Hz, p < 0.01) and activation complexity (1.97 ± 0.45 vs. 2.66 ± 0.58 PS/cm2, p < 0.01) under control conditions. These effects were related to stretch-induced changes affecting the reentrant patterns, comprising a decrease in rotor meandering (0.72 ± 0.12 vs. 0.62 ± 0.12 cm/s, p < 0.001) and an increase in wavefront curvature (4.90 ± 0.42 vs. 5.68 ± 0.40 rad/cm, p < 0.001). Ranolazine reduced stretch-induced effects, attenuating the activation rate increment (12.8% vs. 19.7%, p < 0.01) and maintaining activation complexity-both parameters being lower during stretch than under control conditions. Moreover, under baseline conditions, ranolazine slowed and regularized the activation patterns (3.04 ± 0.61 vs. 3.65 ± 0.69 Hz, p < 0.01). CONCLUSION: Ranolazine attenuates the modifications of activation patterns induced by mechanical stretch in atrial myocyte monolayers.

Noninvasive Assessment of Complexity of Atrial Fibrillation: Correlation With Contact Mapping and Impact of Ablation.

BACKGROUND: It is difficult to noninvasively phenotype atrial fibrillation (AF) in a way that reflects clinical end points such as response to therapy. We set out to map electrical patterns of disorganization and regions of reentrant activity in AF from the body surface using electrocardiographic imaging, calibrated to panoramic intracardiac recordings and referenced to AF termination by ablation. METHODS: Bi-atrial intracardiac electrograms of 47 patients with AF at ablation (30 persistent, 29 male, 63±9 years) were recorded with 64-pole basket catheters and simultaneous 57-lead body surface ECGs. Atrial epicardial electrical activity was reconstructed and organized sites were invasively and noninvasively tracked in 3-dimension using phase singularity. In a subset of 17 patients, sites of AF organization were targeted for ablation. RESULTS: Body surface mapping showed greater AF organization near intracardially detected drivers than elsewhere, both in phase singularity density (2.3±2.1 versus 1.9±1.6; P=0.02) and number of drivers (3.2±2.3 versus 2.7±1.7; P=0.02). Complexity, defined as the number of stable AF reentrant sites, was concordant between noninvasive and invasive methods (r2=0.5; CC=0.71). In the subset receiving targeted ablation, AF complexity showed lower values in those in whom AF terminated than those in whom AF did not terminate (P<0.01). CONCLUSIONS: AF complexity tracked noninvasively correlates well with organized and disorganized regions detected by panoramic intracardiac mapping and correlates with the acute outcome by ablation. This approach may assist in bedside monitoring of therapy or in improving the efficacy of ongoing ablation procedures.

Automatic quality electrogram assessment improves phase-based reentrant activity identification in atrial fibrillation.

Identification of reentrant activity driving atrial fibrillation (AF) is increasingly important to ablative therapies. The goal of this work is to study how the automatically-classified quality of the electrograms (EGMs) affects reentrant AF driver localization. EGMs from 259 AF episodes obtained from 29 AF patients were recorded using 64-poles basket catheters and were manually classified according to their quality. An algorithm capable of identifying signal quality was developed using time and spectral domain parameters. Electrical reentries were identified in 3D phase maps using phase transform and were compared with those obtained with a 2D activation-based method. Effect of EGM quality was studied by discarding 3D phase reentries detected in regions with low-quality EGMs. Removal of reentries identified by 3D phase analysis in regions with low-quality EGMs improved its performance, increasing the area under the ROC curve (AUC) from 0.69 to 0.80. The EGMs quality classification algorithm showed an accurate performance for EGM classification (AUC 0.94) and reentry detection (AUC 0.80). Automatic classification of EGM quality based on time and spectral signal parameters is feasible and accurate, avoiding the manual labelling. Discard of reentries identified in regions with automatically-detected poor-quality EGMs improved the specificity of the 3D phase-based method for AF driver identification.

Perspectives on Directions and Priorities for Future Preclinical Studies in Regenerative Medicine.

The myocardium consists of numerous cell types embedded in organized layers of ECM (extracellular matrix) and requires an intricate network of blood and lymphatic vessels and nerves to provide nutrients and electrical coupling to the cells. Although much of the focus has been on cardiomyocytes, these cells make up <40% of cells within a healthy adult heart. Therefore, repairing or regenerating cardiac tissue by merely reconstituting cardiomyocytes is a simplistic and ineffective approach. In fact, when an injury occurs, cardiac tissue organization is disrupted at the level of the cells, the tissue architecture, and the coordinated interaction among the cells. Thus, reconstitution of a functional tissue must reestablish electrical and mechanical communication between cardiomyocytes and restore their surrounding environment. It is also essential to restore distinctive myocardial features, such as vascular patency and pump function. In this article, we review the current status, challenges, and future priorities in cardiac regenerative or reparative medicine. In the first part, we provide an overview of our current understanding of heart repair and comment on the main contributors and mechanisms involved in innate regeneration. A brief section is dedicated to the novel concept of rejuvenation or regeneration, which we think may impact future development in the field. The last section describes regenerative therapies, where the most advanced and disruptive strategies used for myocardial repair are discussed. Our recommendations for priority areas in studies of cardiac regeneration or repair are summarized in Tables 1 and 2 .

Clinical Characteristics and Electrophysiological Mechanisms Underlying Brugada ECG in Patients With Severe Hyperkalemia.

Background Several metabolic conditions can cause the Brugada ECG pattern, also called Brugada phenotype (BrPh). We aimed to define the clinical characteristics and outcome of BrPh patients and elucidate the mechanisms underlying BrPh attributed to hyperkalemia. Methods and Results We prospectively identified patients hospitalized with severe hyperkalemia and ECG diagnosis of BrPh and compared their clinical characteristics and outcome with patients with hyperkalemia but no BrPh ECG. Computer simulations investigated the roles of extracellular potassium increase, fibrosis at the right ventricular outflow tract, and epicardial/endocardial gradients in transient outward current. Over a 6-year period, 15 patients presented severe hyperkalemia with BrPh ECG that was transient and disappeared after normalization of their serum potassium. Most patients were admitted because of various severe medical conditions causing hyperkalemia. Six (40%) patients presented malignant arrhythmias and 6 died during admission. Multiple logistic regression analysis revealed that higher serum potassium levels (odds ratio, 15.8; 95% CI, 3.1-79; P=0.001) and male sex (odds ratio, 17; 95% CI, 1.05-286; P=0.045) were risk factors for developing BrPh ECG in patients with severe hyperkalemia. In simulations, hyperkalemia yielded BrPh by promoting delayed and heterogeneous right ventricular outflow tract activation attributed to elevation of resting potential, reduced availability of inward sodium channel conductance, and increased right ventricular outflow tract fibrosis. An elevated transient outward current gradient contributed to, but was not essential for, the BrPh phenotype. Conclusions In patients with severe hyperkalemia, a BrPh ECG is associated with malignant arrhythmias and all-cause mortality secondary to resting potential depolarization, reduced sodium current availability, and fibrosis at the right ventricular outflow tract.