Cellular bases for human atrial fibrillation

Atrial fibrillation (AF) causes substantial morbidity and mortality. It may be triggered and sustained by either reentrant or nonreentrant electrical activity. Human atrial cellular refractory period is shortened in chronic AF, likely aiding reentry. The ionic and molecular mechanisms are not fully understood and may include increased inward rectifier K<sup>+</sup> current and altered Ca<sup>2+</sup> handling. Heart failure, a major cause of AF, may involve arrhythmogenic atrial electrical remodeling, but the pattern is unclear in humans. Beta-blocker therapy prolongs atrial cell refractory period; a potentially antiarrhythmic influence, but the ionic and molecular mechanisms are unclear. The search for drugs to suppress AF without causing ventricular arrhythmias has been aided by basic studies of cellular mechanisms of AF. It remains to be seen whether such drugs will improve patient treatment

Atrial cellular electrophysiological changes in patients with ventricular dysfunction may predispose to AF

<b>Background:</b> Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear. Objective This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF. <b>Methods:</b> Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique. <b>Results:</b> The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 ± 8 ms; 52 cells, 18 patients vs 233 ± 7 ms; 134 cells, 49 patients; P <0.05); confirmed by multiple linear regression analysis. The left ventricular ejection fraction (LVEF) was markedly lower in patients with moderate or severe LVSD (36% ± 4%, n = 15) than in those without LVSD (62% ± 2%, n = 31; P <0.05). In cells from patients with LVEF ≤ 45%, the ERP and action potential duration at 90% repolarization were shorter than in those from patients with LVEF > 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P <0.05). The L-type calcium ion current, inward rectifier potassium ion current, and sustained outward ion current were unaffected by LVSD. The transient outward potassium ion current was decreased by 34%, with a positive shift in its activation voltage, and no change in its decay kinetics. <b>Conclusion:</b> LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF

Generation and escape of local waves from the boundary of uncoupled cardiac tissue

We aim to understand the formation of abnormal waves of activity from myocardial regions with diminished cell-to-cell coupling. In route to this goal, we studied the behavior of a heterogeneous myocyte network in which a sharp coupling gradient was placed under conditions of increasing network automaticity. Experiments were conducted in monolayers of neonatal rat cardiomyocytes using heptanol and isoproterenol as means of altering cell-to-cell coupling and automaticity respectively. Experimental findings were explained and expanded using a modified Beeler-Reuter numerical model. The data suggests that the combination of a heterogeneous substrate, a gradient of coupling and an increase in oscillatory activity of individual cells creates a rich set of behaviors associated with self-generated spiral waves and ectopic sources. Spiral waves feature a flattened shape and a pin-unpin drift type of tip motion. These intercellular waves are action-potential based and can be visualized with either voltage or calcium transient measurements. A source/load mismatch on the interface between the boundary and well-coupled layers can lock wavefronts emanating from both ectopic sources and rotating waves within the inner layers of the coupling gradient. A numerical approach allowed us to explore how: i) the spatial distribution of cells, ii) the amplitude and dispersion of cell automaticity, iii) and the speed at which the coupling gradient moves in space, affects wave behavior, including its escape into well-coupled tissue.Comment: 28 pages, 10 figures, submitted to Biophysical Journa

Ionic Mechanisms of Action Potential Rate Dependence, Conduction and Block in Normal Epicardium and in Remodeled Epicardium Post-Infarction

In this work, detailed computational models are used to study the electrophysiology of normal epicardium and the arrhythmogenic effects of epicardial cell remodeling post-infarction. The canine epicardial myocyte model described here reproduces a wide range of experimentally observed rate dependent phenomena in cell and tissue. Model behavior depends on updated formulations for the 4-AP sensitive transient outward current: Ito1), the slow component of the delayed rectifier potassium current: IKs), the L-type Ca2+ channel: ICa,L) and the sodium-potassium pump: INaK) fit to data from canine ventricular myocytes. The model shows that Ito1 plays a limited role in potentiating peak ICa,L and Ca2+ release for propagated action potentials: APs), but modulates the time course of action potential duration: APD) restitution. IKs plays an important role in APD shortening at short diastolic intervals but a limited role in AP repolarization at longer cycle lengths. In addition, simulations demonstrate that ICa,L, INaK and [Na+]i play critical roles in APD accommodation and the rate dependence of APD restitution. Starting from the ionic model of a normal epicardial cell described above, an epicardial border zone: EBZ) model was developed based on available remodeling data. Ionic models of normal zone: NZ) and EBZ myocytes were incorporated into one-dimensional models of propagation to gain mechanistic insight into how ion channel remodeling affects APD and refractoriness, vulnerability to conduction block and conduction safety post-infarction. Simulations of EBZ APD restitution show that remodeled INa and ICaL promote increased effective refractory period: ERP) and prolonged APD at short diastolic interval: DI). Heterogeneous tissue simulations show that increased post-repolarization refractoriness and altered restitution lead to a large rate dependent vulnerable window for conduction block. In simulations of conduction post-infarction, EBZ IK1 remodeling partially offsets the reduction in conduction safety due to altered INa, while Ito1 and ICaL have a negligible effect on conduction. Further simulations show that injection of skeletal muscle sodium channel SkM1-INa, a recently proposed anti-arrhythmic therapy, has several desirable effects including normalization of EBZ ERP and APD restitution, elimination of vulnerability to conduction block and normalization of conduction in uncoupled tissue

Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies

[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito. Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica. Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV). Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit. La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques. La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV. Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates. Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy. Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF. Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI

Up-regulation of the inward rectifier K + current ( I K1 ) in the mouse heart accelerates and stabilizes rotors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65726/1/jphysiol.2006.121475.pd

Electrophysiologic effects of the IK1 inhibitor PA-6 are modulated by extracellular potassium in isolated guinea pig hearts

The pentamidine analog PA‐6 was developed as a specific inward rectifier potassium current (I(K) (1)) antagonist, because established inhibitors either lack specificity or have side effects that prohibit their use in vivo. We previously demonstrated that BaCl(2), an established I(K) (1) inhibitor, could prolong action potential duration (APD) and increase cardiac conduction velocity (CV). However, few studies have addressed whether targeted I(K) (1) inhibition similarly affects ventricular electrophysiology. The aim of this study was to determine the effects of PA‐6 on cardiac repolarization and conduction in Langendorff‐perfused guinea pig hearts. PA‐6 (200 nm) or vehicle was perfused into ex‐vivo guinea pig hearts for 60 min. Hearts were optically mapped with di‐4‐ANEPPS to quantify CV and APD at 90% repolarization (APD (90)). Ventricular APD (90) was significantly prolonged in hearts treated with PA‐6 (115 ± 2% of baseline; P < 0.05), but not vehicle (105 ± 2% of baseline). PA‐6 slightly, but significantly, increased transverse CV by 7%. PA‐6 significantly prolonged APD (90) during hypokalemia (2 mmol/L [K+](o)), although to a lesser degree than observed at 4.56 mmol/L [K+](o). In contrast, the effect of PA‐6 on CV was more pronounced during hypokalemia, where transverse CV with PA‐6 (24 ± 2 cm/sec) was significantly faster than with vehicle (13 ± 3 cm/sec, P < 0.05). These results show that under normokalemic conditions, PA‐6 significantly prolonged APD (90), whereas its effect on CV was modest. During hypokalemia, PA‐6 prolonged APD (90) to a lesser degree, but profoundly increased CV. Thus, in intact guinea pig hearts, the electrophysiologic effects of the I(K) (1) inhibitor, PA‐6, are [K+](o)‐dependent

An improved human ventricular cell model for investigation of cardiac arrhythmias under hyperkalemic conditions

The use of experiments for studying cardiac arrhythmias or the effect of drugs on cardiac electrophysiology is mostly limited to measurements obtained from electrograms (EGMs, measured on the heart surface) or, more often, electrocardiograms (ECGs, measured on the body surface). Despite the fact that many diagnostic and therapeutical decisions rely only upon interpretation of ECG patterns, the cellular and subcellular mechanisms underlying pathophysiological ECG changes remain mostly unclear. Among the different approaches aimed to connect the ECG with its underlying basis, multi-scale computational modeling of the heart arises as a powerful tool to understand cardiac functioning from the ionic to the whole organ level. With the increase in computational resources available to the scientific community, mathematical modeling and simulation of heart's electrical activity is becoming a fundamental tool to understand cardiac behavior. In this study several modifications were introduced to a recently proposed action potential (AP) cell model so as to render it suitable for the study of ventricular arrhythmias. These modifications were based on new experimental data and in the results of several cellular arrhythmic risk biomarkers reported in the literature. Five stimulation protocols were applied to the original and improved models of isolated cell, and a number of cellular arrhythmic risk biomarkers were computed. The stimulation protocol included a steady-state protocol, abrupt changes in cycle length (CL) protocol, S1S2 and dynamic restitution protocols, and concentration rate dependence protocol. In addition, the behavior of the proposed model under hyperkalemic conditions was simulated in a one dimensional fiber by increasing the extracellular [K+], measuring the AP duration (APD), conduction velocity (CV) and effective refractory period (ERP) after steady-state conditions had been reached. Our modifications led to: a) further improved AP triangulation (78:1 ms); b) APD rate adaptation curves characterized by fast and slow time constants within physiological ranges (10:1 s and 105:9 s); c) maximum S1S2 restitution slope in accordance with experimental data (SS1S2 = 1:0). Under hyperkalemia, our results showed that APD progressively decreased with the level of hyperkalemia, while ERP increased after a threshold in the extracellular [K+] was reached ([K+]o = 6mM). Conduction velocity decreased with hyperkalemia and the conduction was blocked above [K+]o = 10:4 mM. Above [K+]o = 9:8mM, alternans appeared in the APD. These results suggest that the longer ERP values and the conduction block above [K+]o = 10:4mM found in the central zone of acutely ischemic tissue as compared to the normal zone could create areas of block that could set a substrate for reentrant arrhythmias