Optical mapping and optogenetics in cardiac electrophysiology research and therapy: a state-of-the-art review.

State-of-the-art innovations in optical cardiac electrophysiology are significantly enhancing cardiac research. A potential leap into patient care is now on the horizon. Optical mapping, using fluorescent probes and high-speed cameras, offers detailed insights into cardiac activity and arrhythmias by analysing electrical signals, calcium dynamics, and metabolism. Optogenetics utilizes light-sensitive ion channels and pumps to realize contactless, cell-selective cardiac actuation for modelling arrhythmia, restoring sinus rhythm, and probing complex cell-cell interactions. The merging of optogenetics and optical mapping techniques for 'all-optical' electrophysiology marks a significant step forward. This combination allows for the contactless actuation and sensing of cardiac electrophysiology, offering unprecedented spatial-temporal resolution and control. Recent studies have performed all-optical imaging ex vivo and achieved reliable optogenetic pacing in vivo, narrowing the gap for clinical use. Progress in optical electrophysiology continues at pace. Advances in motion tracking methods are removing the necessity of motion uncoupling, a key limitation of optical mapping. Innovations in optoelectronics, including miniaturized, biocompatible illumination and circuitry, are enabling the creation of implantable cardiac pacemakers and defibrillators with optoelectrical closed-loop systems. Computational modelling and machine learning are emerging as pivotal tools in enhancing optical techniques, offering new avenues for analysing complex data and optimizing therapeutic strategies. However, key challenges remain including opsin delivery, real-time data processing, longevity, and chronic effects of optoelectronic devices. This review provides a comprehensive overview of recent advances in optical mapping and optogenetics and outlines the promising future of optics in reshaping cardiac electrophysiology and therapeutic strategies.

Shining light on cardiac electrophysiology: From detection to intervention, from basic research to translational applications.

Cardiac arrhythmias are an important group of cardiovascular diseases, which can occur alone or in association with other cardiovascular diseases. The development of cardiac arrhythmias cannot be separated from changes in cardiac electrophysiology, and the investigation and clarification of cardiac electrophysiological changes are beneficial for the treatment of cardiac arrhythmias. However, electrical energy-based pacemakers and defibrillators, which are widely used to treat arrhythmias, still have certain disadvantages. Thereby, optics promises to be used for optical manipulation and its use in biomedicine is increasing. Since visible light is readily absorbed and scattered in living tissues and tissue penetration is shallow, optical modulation for cells and tissues requires conversion media that convert light energy into bioelectrical activity. In this regard, fluorescent dyes, light-sensitive ion channels, and optical nanomaterials can assume this role, the corresponding optical mapping technology, optogenetics technology, and optical systems based on luminescent nanomaterials have been introduced into the research in cardiovascular field and are expected to be new tools for the study and treatment of cardiac arrhythmias. In addition, infrared and near-infrared light has strong tissue penetration, which is one of the excellent options of external trigger for achieving optical modulation, and is also widely used in the study of optical modulation of biological activities. Here, the advantages of optical applications are summarized, the research progresses and emerging applications of optical-based technologies as detection and intervention tools for cardiac electrophysiological are highlighted. Moreover, the prospects for future applications of optics in clinical diagnosis and treatment are discussed.

Non-paroxysmal atrial fibrillation mapping: characterization of the electrophysiological substrate using a novel integrated mapping technique.

AIMS: Clinical outcomes after radiofrequency catheter ablation (RFCA) remain suboptimal in the treatment of non-paroxysmal atrial fibrillation (AF). Electrophysiological mapping may improve understanding of the underlying mechanisms. To describe the arrhythmia substrate in patients with persistent (Pers) and long-standing persistent (LSPers) AF, undergoing RFCA, using an integrated mechanism mapping technique. METHODS AND RESULTS: Patients underwent high-density electroanatomical mapping before and after catheter ablation. Integrated maps characterized electrogram (EGM) cycle length (CL) in regions with repetitive-regular (RR) activations, stable wavefront propagation, fragmentation, and peak-to-peak bipolar voltage. Among 83 patients (72% male, 60 ± 11 years old), RR activations were identified in 376 regions (mean CL 180 ± 31 ms). PersAF patients (n = 43) showed more RR sites per patient (5.3 ± 2.4 vs. 3.7 ± 2.1, P = 0.002) with faster CL (166 ± 29 vs. 190 ± 29 ms; P < 0.001) and smaller surface area of fragmented EGMs (15 ± 14% vs. 27 ± 17%, P < 0.001) compared with LSPersAF. The post-ablation map in 50 patients remaining in AF, documented reduction of the RR activities per patient (1.5 ± 0.7 vs. 3.7 ± 1.4, P < 0.001) and area of fragmentation (22 ± 17% vs. 8 ± 9%, P < 0.001). Atrial fibrillation termination during ablation occurred at RR sites (0.48 ± 0.24 mV; 170.5 ± 20.2 ms CL) in 31/33 patients (94%). At the latest follow-up, arrhythmia freedom was higher among patients receiving ablation >75% of RR sites (Q4 82.6%, Q3 63.1%, Q2 35.1%, and Q1 0%; P < 0.001). CONCLUSION: The integrated mapping technique allowed characterization of multiple arrhythmic substrates in non-paroxysmal AF patients. This technique might serve as tool for a substrate-targeted ablation approach.

Electrophysiological Measurement of Rat Atrial Epicardium Using a Novel Stereotaxic Apparatus.

Flexible, in vivo maneuverable electrophysiology mapping techniques are not available in rat models. A novel cardiac stereotactic electrophysiology epicardial mapping system (CREAMS) allows for various measurements, including: (1) recording unipolar electrograms at multiple sites; (2) positioning of mapped sites and precision testing (Distance between the two "centers" = 297 ± 54 µm, n = 15); (3) evaluation of electrophysiology in an in vivo Sprague-Dawley rat model with high-frequency stimulation (HFS)-induced Atrial fibrillation (AF) at high right atrium (HRA) sites. We found that of the right atrium dispersion of effective refractory period (P < 0.05) and the window of vulnerability (P < 0.01) were significantly increased (P < 0.05) after HRA HFS. CREAMS has the potential for convenient electrophysiology assessment in a rat AF model through stereo-positioning, and flexible operating manipulation.

Organic Electrochemical Transistor Arrays for In Vitro Electrophysiology Monitoring of 2D and 3D Cardiac Tissues.

Here, a multichannel organic electrochemical transistor (OECT) array is reported for electrophysiological monitoring and mapping of action potential propagation of a wide range of cardiac cells, including cell lines, primary cell lines, and human-sourced stem cell derivatives in 2D and 3D structures. The results suggest that the ability to exploit this OECT-based platform to map 2D action potential propagation provides a viable strategy to better characterize cardiac cells in response to various chronotropic drugs. The effects of chronotropic agents Isoproterenol and Verapamil on cardiac tissues validate the utility of OECT for drug screening capability, and a preliminary demonstration of a 64-channel OECT array to monitor the cardiac action potentials for better spatial resolution is presented. The study demonstrates that OECT will be a viable and versatile platform for applications in medical and pharmacological industries.

Video Caso Clínico: Estimulación Vagal Directa Como Maniobra Electrofisiológica Alternativa en el Diagnóstico de Taquicardia Durante Estudio Electrofisiológico / Case Report: Direct Vagal Stimulation as Alternative Electrophysiological Procedure in the Diagnosis of Tachycardias During Electrophysiological Study

INTRODUCCIÓN: El síndrome de Wolff Parkinson White se caracteriza por la conexión anómala entre la aurícula y el ventrículo durante el paso del estímulo sinusal, generalmente causada por una vía accesoria que conecta el músculo auricular con el músculo ventricular llamado haz de Kent, caracterizándose por la presencia de síntomas como: palpitaciones, sincope o muerte súbita y sumado a la presencia de onda delta, intervalo PR corto, QRS ancho y alteraciones de la repolarización ventricular en el electrocardiograma. El estudio electrofisiológico tiene como objetivo confirmar la presencia, localización y características de este haz anómalo y posteriormente, con seguridad, proceder a la ablación por radiofrecuencia eliminando esta vía accesoria, siendo considerado un procedimiento curativo en el caso del síndrome de Wolff Parkinson White. Durante el estudio se realiza estimulaciones eléctricas en los sitios específicos, tanto de la aurícula como del ventrículo, además se utiliza medicación intravenosa como la adenosina que actúa bloqueando al nódulo aurículoventricular y así observar el paso residual de la estimulación sinusal normal y/o el paso retrogrado del estímulo ventricular hacia la aurícula a través del haz de Kent, permitiendo de esta forma analizar las características de las conexiones aurículoventriculares previo a la ablación. La posibilidad de realizar una estimulación vagal selectiva de alta frecuencia y baja amplitud a nivel infraorbitario, descrita por Pachón et al [1], a través de la vena yugular interna y el consecuente bloqueo aurículoventricular transitorio que esta ocasiona, permite realizar el estudio sin necesidad de utilizar otras maniobras electrofisiológicas o medicación endovenosa

BACKGROUND: Wolff Parkinson White Syndrome is characterized by the bypass of the electrical signal through an abnormal pathway, different from the atrioventricular node that connects the atrial and ventricular muscles (Bundle of Kent). It presents with palpitations, syncope or can even cause sudden death. Electrocardiogram findings consist on Delta waves, shortened PR interval, widened QRS complex and altering of the ventricular repolarization. In the presence of Ventricular pre-excitation (Wolff Parkinson White Syndrome), the electrophysiological testing is key to confirm the presence, site and features of this accessory pathway. Later, with the certainty of the diagnosis proceed to perform the Radiofrequency Ablation, the definitive treatment to eliminate this abnormal pathway. This test is usually done with the use of electrophysiological maneuvers, stimulating key sites in the atria and the ventricle, with the help of intravenous drugs like Adenosine. The objective is to block the AV node to look how the remnants of the normal electrical signal move through the abnormal pathway, thus letting the physician analyze the characteristics previously mentioned of this pathway. After the ablation, these maneuvers are repeated to confirm the complete elimination of the accessory pathway that has direct relation with the prognostic. Based on the possibility of high frequency and low amplitude selective vagal stimulation described by Pachón et al [1], at infraorbital level through the internal jugular vein and the resulting transitory atrioventricular block. It is possible to study the abnormal pathway without the need of electrophysiological maneuvers or the use of IV drugs, either pre or post ablation.

Development of a rapid and economic in vivo electrocardiogram platform for cardiovascular drug assay and electrophysiology research in adult zebrafish.

Zebrafish is a popular and favorable model organism for cardiovascular research, with an increasing number of studies implementing functional assays in the adult stage. For example, the application of electrocardiography (ECG) in adult zebrafish has emerged as an important tool for cardiac pathophysiology, toxicity, and chemical screen studies. However, few laboratories are able to perform such functional analyses due to the high cost and limited availability of a convenient in vivo ECG recording system. In this study, an inexpensive ECG recording platform and operation protocol that has been optimized for adult zebrafish ECG research was developed. The core hardware includes integration of a ready-to-use portable ECG kit with a set of custom-made needle electrode probes. A combined anesthetic formula of MS-222 and isoflurane was first tested to determine the optimal assay conditions to minimize the interference to zebrafish cardiac physiology under sedation. For demonstration, we treated wild-type zebrafish with different pharmacological agents known to affect cardiac rhythms in humans. Conserved electrophysiological responses to these drugs were induced in adult zebrafish and recorded in real time. This economic ECG platform has the potential to facilitate teaching and training in cardiac electrophysiology with adult zebrafish and to promote future translational applications in cardiovascular medicine.

Inhomogeneity and complexity in defining fractionated electrograms.

Ablation strategies targeting areas of complex fractionated atrial electrograms are not successful for treatment of atrial fibrillation. Fractionation of atrial electrograms may have multiple causes of both pathologic and nonpathologic origin. In order to gain insight into the definitions used for determining areas of fractionation, a literature search was performed using a systematic approach. A PubMed search for studies describing fractionation during human atrial electrophysiologic measurements resulted in 348 articles that were screened for new definitions of fractionation. The 24 studies remaining after screening described 11 different visual definitions for fractionation, 3 automated complex fractionated atrial electrogram detection programs, and 7 new parameters for measuring fractionation. Five different definitions for continuous electrical activity were presented. Electrode properties were often not described, and endocardial bipolar recordings in recent studies used electrode diameters ranging from 1 to 8 mm with interelectrode distance of 2-5 mm. In summary, no uniform definition or recording method is used for measuring fractionation of cardiac atrial electrograms. The different electrophysiologic causes of fractionation and the influence of recording device properties on fractionation complicate identification of true pathologic inhomogeneous conduction. The first step in discrimination between origins of fractionation may be accomplished by relating electrogram morphology to spatial patterns of activation. Before revisiting ablation of areas with fractionated electrograms, we need to determine the correct method for identifying pathologic fractionation.

Indices of bipolar complex fractionated atrial electrograms correlate poorly with each other and atrial fibrillation substrate complexity.

BACKGROUND: The pathophysiological relevance of complex fractionated atrial electrograms (CFAE) in atrial fibrillation (AF) remains poorly understood. OBJECTIVE: The aim of this study was to comprehensively investigate how bipolar CFAE correlates with unipolar electrogram fractionation and the underlying electrophysiological substrate of AF. METHODS: Ten-second unipolar AF electrograms were recorded using a high-density electrode from the left atrium of 20 patients with AF (10 with persistent AF and 10 with paroxysmal AF) undergoing cardiac surgery. Semiautomated bipolar CFAE algorithms: complex fractionated electrogram-mean, interval confidence interval, continuous electrical activity, average complex interval, and shortest complex interval were evaluated against AF substrate complexity measures following fibrillation wave reconstruction derived from local unipolar activation time. The effect of interelectrode spacing and electrode orientation on bipolar CFAE was also examined. RESULTS: All 5 semiautomated bipolar CFAE algorithms showed poor correlation with each other and AF substrate complexity measures (conduction velocity, number of waves or breakthroughs per AF cycle, and electrical dissociation). Bipolar CFAE also correlated poorly with fractionation index derived from unipolar electrograms. Increased interelectrode spacing resulted in an increase in bipolar CFAE detected except for the interval confidence interval algorithm. CFAE appears unaffected by bipolar electrode orientation (vertical vs horizontal). By contrast, unipolar fractionation index correlated well with AF substrate complexity measures and can be regarded as a marker for conduction block. CONCLUSION: The lack of pathophysiological relevance of bipolar CFAE analysis may in part contribute to the divergent and limited success rates of catheter ablation strategies targeting CFAE.

Diagnóstico diferencial entre doble respuesta ventricular y extrasistolia hisiana bigeminada. Respuesta / Differential diagnosis between dual ventricular response and bigeminy arising from the bundle of his. Response

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Cardiac electrophysiological imaging systems scalable for high-throughput drug testing.

Multi-parametric electrophysiological measurements using optical methods have become a highly valued standard in cardiac research. Most published optical mapping systems are expensive and complex. Although some applications demand high-cost components and complex designs, many can be tackled with simpler solutions. Here, we describe (1) a camera-based voltage and calcium imaging system using a single 'economy' electron-multiplying charge-coupled device camera and demonstrate the possibility of using a consumer camera for imaging calcium transients of the heart, and (2) a photodiode-based voltage and calcium high temporal resolution measurement system using single-element photodiodes and an optical fibre. High-throughput drug testing represents an application where system scalability is particularly attractive. Therefore, we tested our systems on tissue exposed to a well-characterized and clinically relevant calcium channel blocker, nifedipine, which has been used to treat angina and hypertension. As experimental models, we used the Langendorff-perfused whole-heart and thin ventricular tissue slices, a preparation gaining renewed interest by the cardiac research community. Using our simplified systems, we were able to monitor simultaneously the marked changes in the voltage and calcium transients that are responsible for the negative inotropic effect of the compound.

Síndromes de la onda J / J wave syndromes

Se realizó una revisión sobre los aspectos más novedosos y polémicos de los síndromes de la onda J, que incluyó el síndrome de repolarización precoz, la fibrilación ventricular idiopática y la muerte súbita nocturna inexplicable. Se enfatiza en las características electrocardiográficas de estos síndromes donde se destaca la presencia de un supradesnivel del ST tipo cóncavo con melladuras o empastamiento del mismo. Se profundiza en las bases genéticas, a veces común a todos ellos, en particular la mutación SCN5A asociada con el supradesnivel del ST y más recientemente la mutación S422L-KCNJ8 como causa de alteración de los canales I K-ATP, lo cual se asocia con mortalidad arrítmica cardíaca. Se concluye que aunque no todos los pacientes con este síndrome estén en riesgo de eventos arrítmicos o de muerte súbita cardíaca, existe un grupo de ellos no despreciable que sí lo están, por lo que el gran desafío de la comunidad médica es desarrollar mejores estrategias de estratificación de riesgo y desarrollar tratamientos más seguros y eficaces para estos(AU)

A review was conducted of the newest and most controversial aspects of J wave syndromes, including early repolarization syndrome, idiopathic ventricular fibrillation and sudden unexplained nocturnal death. Emphasis is made on the ECG features of these syndromes, among them the presence of an upwardly concave ST irregularity with notching or slurring. A detailed analysis is made of genetic bases, which are sometimes common to all syndromes, particularly the SCN5A mutation, associated with the ST upwardly irregularity, and more recently the S422L-KCNJ8 mutation causing the alteration in the lK-ATP channels, associated with arrhythmic cardiac mortality. It is concluded that not all patients with this syndrome are at risk of arrhythmic events or sudden cardiac death, but a significant number of them are. Therefore, a great challenge for the medical community is to develop better risk stratification strategies as well as safer and more effective treatments(AU)

Síndromes de la onda J / J wave syndromes

Se realizó una revisión sobre los aspectos más novedosos y polémicos de los síndromes de la onda J, que incluyó el síndrome de repolarización precoz, la fibrilación ventricular idiopática y la muerte súbita nocturna inexplicable. Se enfatiza en las características electrocardiográficas de estos síndromes donde se destaca la presencia de un supradesnivel del ST tipo cóncavo con melladuras o empastamiento del mismo. Se profundiza en las bases genéticas, a veces común a todos ellos, en particular la mutación SCN5A asociada con el supradesnivel del ST y más recientemente la mutación S422L-KCNJ8 como causa de alteración de los canales I K-ATP, lo cual se asocia con mortalidad arrítmica cardíaca. Se concluye que aunque no todos los pacientes con este síndrome estén en riesgo de eventos arrítmicos o de muerte súbita cardíaca, existe un grupo de ellos no despreciable que sí lo están, por lo que el gran desafío de la comunidad médica es desarrollar mejores estrategias de estratificación de riesgo y desarrollar tratamientos más seguros y eficaces para estos

A review was conducted of the newest and most controversial aspects of J wave syndromes, including early repolarization syndrome, idiopathic ventricular fibrillation and sudden unexplained nocturnal death. Emphasis is made on the ECG features of these syndromes, among them the presence of an upwardly concave ST irregularity with notching or slurring. A detailed analysis is made of genetic bases, which are sometimes common to all syndromes, particularly the SCN5A mutation, associated with the ST upwardly irregularity, and more recently the S422L-KCNJ8 mutation causing the alteration in the lK-ATP channels, associated with arrhythmic cardiac mortality. It is concluded that not all patients with this syndrome are at risk of arrhythmic events or sudden cardiac death, but a significant number of them are. Therefore, a great challenge for the medical community is to develop better risk stratification strategies as well as safer and more effective treatments

[The assessment of reactions of polygraphic parameters at HRV-biofeedback training in adolescents with different variants of cardiac autonomic nervous system tone].

There is examine a character of change of brain bioelectric activity and polygraphic indicators at sessions of biofeedback by heart rhythm variability parameters (HRV-biofeedback) in 15-17 years adolescents who have different variants of cardiac autonomic nervous system tone. It is taped, that adolescents with cardiac balanced tone have more intensive optimization of functional brain activity in comparison with adolescents who have cardiac sympathetic tone - increase on alpha-activity and theta-activity depression in electroencephalogram structure. There were optimization of neurodynamic processes and most expressed stabilization of the hemodynamics indicators in adolescents with cardiac sympathetic tone after HRV-biofeedback training.

Computational modelling of cardiac electrophysiology: explanation of the variability of results from different numerical solvers.

A recent verification study compared 11 large-scale cardiac electrophysiology solvers on an unambiguously defined common problem. An unexpected amount of variation was observed between the codes, including significant error in conduction velocity in the majority of the codes at certain spatial resolutions. In particular, the results of the six finite element codes varied considerably despite each using the same order of interpolation. In this present study, we compare various algorithms for cardiac electrophysiological simulation, which allows us to fully explain the differences between the solvers. We identify the use of mass lumping as the fundamental cause of the largest variations, specifically the combination of the commonly used techniques of mass lumping and operator splitting, which results in a slightly different form of mass lumping to that supported by theory and leads to increased numerical error. Other variations are explained through the manner in which the ionic current is interpolated. We also investigate the effect of different forms of mass lumping in various types of simulation.

Reduced-order modeling for cardiac electrophysiology. Application to parameter identification.

A reduced-order model based on proper orthogonal decomposition (POD) is proposed for the bidomain equations of cardiac electrophysiology. Its accuracy is assessed through electrocardiograms in various configurations, including myocardium infarctions and long-time simulations. We show in particular that a restitution curve can efficiently be approximated by this approach. The reduced-order model is then used in an inverse problem solved by an evolutionary algorithm. Some attempts are presented to identify ionic parameters and infarction locations from synthetic electrocardiograms.