Exploring the potential of omics technologies in medicinal plant research: a review in Colombia / Explorando el potencial de las tecnologías ómicas en la investigación de plantas medicinales: una revisión en Colombia

This review presents advances in the implementation of high - throughput se quencing and its application to the knowledge of medicinal plants. We conducted a bibliographic search of papers published in PubMed, Science Direct, Google Scholar, Scopus, and Web of Science databases and analyzed the obtained data using VOSviewer (versi on 1.6.19). Given that medicinal plants are a source of specialized metabolites with immense therapeutic values and important pharmacological properties, plant researchers around the world have turned their attention toward them and have begun to examine t hem widely. Recent advances in sequencing technologies have reduced cost and time demands and accelerated medicinal plant research. Such research leverages full genome sequencing, as well as RNA (ribonucleic acid) sequencing and the analysis of the transcr iptome, to identify molecular markers of species and functional genes that control key biological traits, as well as to understand the biosynthetic pathways of bioactive metabolites and regulatory mechanisms of environmental responses. As such, the omics ( e.g., transcriptomics, metabolomics, proteomics, and genomics, among others) have been widely applied within the study of medicinal plants, although their usage in Colombia is still few and, in some areas, scarce. (185)

El extracto de cloroformo (CE) y las fracciones obtenidas de las raíces de Aldama arenaria se evaluaron para determinar su actividad antiproliferativa in vitro contra 10 líneas ce lulares tumorales humanas [leucemia (K - 562), mama (MCF - 7), ovario que expresa un fenotipo resistente a múltiples fármacos (NCI/ADR - RES), melanoma (UACC - 62), pulmón (NCI - H460), próstata (PC - 3), colon (HT29), ovario (OVCAR - 3), glioma (U251) y riñón (786 - 0)]. CE presentó actividad antiproliferativa débil a moderada (log GI 50 medio 1.07), mientras que las fracciones 3 y 4, enriquecidas con diterpenos de tipo pimarane [ent - pimara - 8 (14), ácido 15 - dien - 19 - oico y ent - 8(14),15 - pimaradien - 3 ß - ol], presentaron activid ad moderada a potente para la mayoría de las líneas celulares, con un log GI 50 medio de 0.62 y 0.59, respectivamente. Los resultados mostraron una acción antiproliferativa in vitro prometedora de las muestras obtenidas de A. arenaria , con los mejores resul tados para NCI/ADR - RES, HT29 y OVCAR - 3, y valores de TGI que van desde 5.95 a 28.71 µg.mL - 1, demostrando que los compuestos de esta clase pueden ser prototipos potenciales para el descubrimiento de nuevos agentes terapéuticos

Pro-arrhythmic effects of low plasma [K+] in human ventricle: An illustrated review.

Potassium levels in the plasma, [K+]o, are regulated precisely under physiological conditions. However, increases (from approx. 4.5 to 8.0mM) can occur as a consequence of, e.g., endurance exercise, ischemic insult or kidney failure. This hyperkalemic modulation of ventricular electrophysiology has been studied extensively. Hypokalemia is also common. It can occur in response to diuretic therapy, following renal dialysis, or during recovery from endurance exercise. In the human ventricle, clinical hypokalemia (e.g., [K+]o levels of approx. 3.0mM) can cause marked changes in both the resting potential and the action potential waveform, and these may promote arrhythmias. Here, we provide essential background information concerning the main K+-sensitive ion channel mechanisms that act in concert to produce prominent short-term ventricular electrophysiological changes, and illustrate these by implementing recent mathematical models of the human ventricular action potential. Even small changes (~1mM) in [K+]o result in significant alterations in two different K+ currents, IK1 and HERG. These changes can markedly alter in resting membrane potential and/or action potential waveform in human ventricle. Specifically, a reduction in net outward transmembrane K+ currents (repolarization reserve) and an increased substrate input resistance contribute to electrophysiological instability during the plateau of the action potential and may promote pro-arrhythmic early after-depolarizations (EADs). Translational settings where these insights apply include: optimal diuretic therapy, and the interpretation of data from Phase II and III trials for anti-arrhythmic drug candidates.

Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour.

In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).

Changes in Intracellular Na+ following Enhancement of Late Na+ Current in Virtual Human Ventricular Myocytes.

The slowly inactivating or late Na+ current, INa-L, can contribute to the initiation of both atrial and ventricular rhythm disturbances in the human heart. However, the cellular and molecular mechanisms that underlie these pro-arrhythmic influences are not fully understood. At present, the major working hypothesis is that the Na+ influx corresponding to INa-L significantly increases intracellular Na+, [Na+]i; and the resulting reduction in the electrochemical driving force for Na+ reduces and (may reverse) Na+/Ca2+ exchange. These changes increase intracellular Ca2+, [Ca2+]i; which may further enhance INa-L due to calmodulin-dependent phosphorylation of the Na+ channels. This paper is based on mathematical simulations using the O'Hara et al (2011) model of baseline or healthy human ventricular action potential waveforms(s) and its [Ca2+]i homeostasis mechanisms. Somewhat surprisingly, our results reveal only very small changes (≤ 1.5 mM) in [Na+]i even when INa-L is increased 5-fold and steady-state stimulation rate is approximately 2 times the normal human heart rate (i.e. 2 Hz). Previous work done using well-established models of the rabbit and human ventricular action potential in heart failure settings also reported little or no change in [Na+]i when INa-L was increased. Based on our simulations, the major short-term effect of markedly augmenting INa-L is a significant prolongation of the action potential and an associated increase in the likelihood of reactivation of the L-type Ca2+ current, ICa-L. Furthermore, this action potential prolongation does not contribute to [Na+]i increase.

Lessons learned from multi-scale modeling of the failing heart.

Heart failure constitutes a major public health problem worldwide. Affected patients experience a number of changes in the electrical function of the heart that predispose to potentially lethal cardiac arrhythmias. Due to the multitude of electrophysiological changes that may occur during heart failure, the scientific literature is complex and sometimes ambiguous, perhaps because these findings are highly dependent on the etiology, the stage of heart failure, and the experimental model used to study these changes. Nevertheless, a number of common features of failing hearts have been documented. Prolongation of the action potential (AP) involving ion channel remodeling and alterations in calcium handling have been established as the hallmark characteristics of myocytes isolated from failing hearts. Intercellular uncoupling and fibrosis are identified as major arrhythmogenic factors. Multi-scale computational simulations are a powerful tool that complements experimental and clinical research. The development of biophysically detailed computer models of single myocytes and cardiac tissues has contributed greatly to our understanding of processes underlying excitation and repolarization in the heart. The electrical, structural, and metabolic remodeling that arises in cardiac tissues during heart failure has been addressed from different computational perspectives to further understand the arrhythmogenic substrate. This review summarizes the contributions from computational modeling and simulation to predict the underlying mechanisms of heart failure phenotypes and their implications for arrhythmogenesis, ranging from the cellular level to whole-heart simulations. The main aspects of heart failure are presented in several related sections. An overview of the main electrophysiological and structural changes that have been observed experimentally in failing hearts is followed by the description and discussion of the simulation work in this field at the cellular level, and then in 2D and 3D cardiac structures. The implications for arrhythmogenesis in heart failure are also discussed including therapeutic measures, such as drug effects and cardiac resynchronization therapy. Finally, the future challenges in heart failure modeling and simulation will be discussed.

LOCALIZACIÓN DE FOCOS ECTÓPICOS DURANTE FIBRILACIÓN AURICULAR PERMANENTE, MEDIANTE UN NUEVO ÍNDICE OHF. ESTUDIO DE SIMULACIÓN / ECTOPIC FOCI LOCATION DURING PERMANENT ATRIAL FIBRILLATION USING A NEW INDEX OHF. A SIMULATION STUDY / LOCALIZAÇÃO DE FOCOS ECTÓPICOS DURANTE FIBRILAÇÃO ATRIAL PERMANENTE EM UM NOVO ÍNDICE OHF. ESTUDO DE SIMULAÇÃO

La fibrilación auricular (FA), en ciertos casos, es mantenida por focos ectópicos de actividad automática, organización espacio temporal y de alta frecuencia. La ablación de estos sitios da como resultado la terminación de la FA en un alto porcentaje en paciente con FA paroxística, sin embargo, en pacientes con FA permanente estos sitios son difíciles de reconocer debido a la capacidad de las aurículas remodeladas para ser activadas a altas frecuencias. Es necesario un método más preciso para acotar mejor estas zonas. En el presente trabajo se plantea desarrollar un nuevo índice, a partir de los índices de frecuencia dominante (DF) e índice de organización (IO), para la identificación de estas zonas. Para esto, se simularon episodios de FA permanente mantenidos por focos ectópicos de actividad continua en tres diferentes regiones, implementando un modelo 3D de aurícula humana. Se obtuvieron electrogramas en toda la superficie auricular y se calculó su DF and IO. El índice OHF (Organization High Frequency), se calculó como el producto entre el valor de la DF y del IO de cada uno de los electrogramas y se crearon mapas de falso color sobre el modelo 3D. Los resultados muestran que el índice OHF es capaz de identificar el foco ectópico de actividad continua durante episodios de FA permanente simulados.

Atrial fibrillation in some cases is maintained by ectopic foci with automatic activity, spatiotemporal organization and high frequency. Ablating these sites results in the AF termination in a high percentage of patients with paroxysmal AF, however, in patients with permanent AF these sites are difficult to recognize due to the ability of the remodeled atria to be activated at high frequencies. A more accurate method is needed to delimit better these areas. In the present work, we developed a new index, based on dominant frequency (DF) and organization index (OI), to identify these areas. For this, we simulated permanent AF episodes maintained by ectopic foci with continuous activity in three different regions, implementing a 3D model of human atrium. Electrograms were obtained across the atrial surface and its DF and IO were calculated. The OHF index (Organization High Frequency), was calculated as the product of the DF and IO values of individual electrograms and we created false color maps in the 3D model. The results show that the OHF index is able to identify ectopic foci of continuous activity during simulated permanent AF episodes.

A fibrilação atrial (FA), em alguns casos, é mantida por focos de actividade ectópica automático, organização e espaço de alta frequência temporal. Ablação desses locais determina a resolução da FA em uma alta porcentagem de pacientes com FA paroxística, no entanto, em pacientes com fibrilação atrial permanente desses sites são difíceis de reconhecer devido à capacidade dos átrios remodelado para ser ativado em alta frequências. Essas áreas para melhor abordagem é necessário um limite mais preciso. Neste artigo propõe-se a desenvolver uma freqüência novos índices com base em índice dominante (DF) e índice de organização (OI) para a identificação dessas áreas. Para isso, episódios de FA permanente mantido por focos ectópicos de atividade contínua em três regiões diferentes, implementando um modelo 3D de átrios humanos foram simulados. Eletrocardiogramas foram obtidos ao longo da superfície auricular e calculado o DF e IO. O OHF (Organização High Frequency) índice foi calculado como o produto do valor do DF e IO de eletrocardiogramas individuais e falsos mapas de cores do modelo 3D é criado. Os resultados mostram que o índice de OHF é capaz de identificar o foco ectópico de actividade contínua durante episódios de FA permanentes simulados.

Electrophysiological and structural remodeling in heart failure modulate arrhythmogenesis. 1D simulation study.

BACKGROUND: Heart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression. OBJECTIVE: In this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation. METHODS: Two different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias. RESULTS: Simulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+/Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure. CONCLUSION: An extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this. Furthermore, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In combination these changes set the stage for arrhythmias.

Electrophysiological and structural remodeling in heart failure modulate arrhythmogenesis. 2D simulation study.

BACKGROUND: Heart failure is operationally defined as the inability of the heart to maintain blood flow to meet the needs of the body and it is the final common pathway of various cardiac pathologies. Electrophysiological remodeling, intercellular uncoupling and a pro-fibrotic response have been identified as major arrhythmogenic factors in heart failure. OBJECTIVE: In this study we investigate vulnerability to reentry under heart failure conditions by incorporating established electrophysiological and anatomical remodeling using computer simulations. METHODS: The electrical activity of human transmural ventricular tissue (5 cm × 5 cm) was simulated using the human ventricular action potential model Grandi et al. under control and heart failure conditions. The MacCannell et al. model was used to model fibroblast electrical activity, and their electrotonic interactions with myocytes. Selected degrees of diffuse fibrosis and variations in intercellular coupling were considered and the vulnerable window (VW) for reentry was evaluated following cross-field stimulation. RESULTS: No reentry was observed in normal conditions or in the presence of HF ionic remodeling. However, defined amount of fibrosis and/or cellular uncoupling were sufficient to elicit reentrant activity. Under conditions where reentry was generated, HF electrophysiological remodeling did not alter the width of the VW. However, intermediate fibrosis and cellular uncoupling significantly widened the VW. In addition, biphasic behavior was observed, as very high fibrotic content or very low tissue conductivity hampered the development of reentry. Detailed phase analysis of reentry dynamics revealed an increase of phase singularities with progressive fibrotic components. CONCLUSION: Structural remodeling is a key factor in the genesis of vulnerability to reentry. A range of intermediate levels of fibrosis and intercellular uncoupling can combine to favor reentrant activity.

EFECTO DEL FÁRMACO CLOROQUINA EN LA TERMINACIÓN DE UN ROTOR DURANTE FIBRILACIÓN AURICULAR PAROXÍSTICA. ESTUDIO DE SIMULACIÓN / CHLOROQUINE DRUG EFFECT ON A ROTOR TERMINATION DURING PAROXYSMAL ATRIAL FIBRILLATION. A SIMULATION STUDY / O EFEITO DO MEDICAMENTO CLOROQUINA NO FECHAMENTO DE UM ROTOR DURANTE FIBRILAÇÃO ATRIAL PAROXÍSTICA. SIMULAÇÃO ESTUDO

La fibrilación auricular (FA) es la arritmia más común. Algunos episodios de FA son mantenidos por rotores. La FA paroxística (FAp) se refiere a episodios recurrentes que se autolimitan. Si la FAp no se trata puede convertirse en crónica. Se ha demostrado que la inhibición de las corrientes I KACh e I K1 contribuye a la terminación de la FA. El fármaco antimalárico cloroquina, al inhibir estas corrientes podría ser un fármaco antiarrítmico eficaz en humanos. El objetivo del trabajo es simular los efectos de la cloroquina y estudiar su eficacia en la terminación de un rotor en condiciones de FAp. Para esto, se desarrolló un modelo 2D de tejido auricular en condiciones de FAp. Se implementó un modelo del efecto de la cloroquina sobre las corrientes I K1 e I KACh para estudiar su eficacia en la terminación de un rotor simulado. La cloroquina alargó el potencial de acción a medida que se incrementó su concentración. A concentraciones de 0.3 µM y superiores, finalizó la actividad del rotor. Este es el primer trabajo que ha desarrollado modelos matemáticos del fármaco cloroquina para estudiar su efecto en la terminación de un rotor. Los resultados sugieren que la cloroquina podría ser un potente agente antiarrítmico en el tratamiento de la FAp.

Atrial fibrillation (AF) is the most common arrhythmia. Some AF episodes are maintained by rotors. Paroxysmal AF (pAF) refers to self-limiting recurrent episodes. If the pAF is not treated it could become chronic. It has been demonstrated that inhibition of the I K1 and I KACh currents contributes to AF termination. Antimalarial drug chloroquine by inhibiting these currents could be an effective antiarrhythmic drug in humans. The aim of this work is to simulate the effects of chloroquine and study their effectiveness in the rotor termination in pAF conditions. For this, we developed a 2D model of atrial tissue under pAF conditions. We implemented a model of the effect of chloroquine on I K1 and I KACh currents to study its effectiveness in the termination of a simulated rotor. Chloroquine lengthened the action potential as the concentration increased. At concentrations of 0.3 µM and higher, the activity of the rotor finished. This is the first work that developed a chloroquine mathematical models to study its effect on the rotor termination. The results suggest that chloroquine could be a potent antiarrhythmic drug for the pAF treatment.

A fibrilhação auricular (FA) é a arritmia mais comum. Alguns episódios de FA são mantidos por rotores. A FA paroxística (FAp) refere-se a episódios recorrentes que são autolimitantes. Se a FAP não tem nenhum tratamento, pode se tornar crônica. Tem sido demonstrado que a inibição das correntes I KACh e I K1 contribui para o término da AF. O medeicamento antimalárico cloroquina, para inibir essas correntes poderia ser um medicamento anti-arrítmico eficaz em seres humanos. O objetivo deste trabalho é simular os efeitos da cloroquina e estudar a sua eficácia na terminação de um rotor capaz em condições FAp. Para isso, um modelo 2D foi desenvolvido de tecido auricular em condições de FAp. foi implementado um modelo do efeito da Cloroquina sobre as corrente I K1 e I KACh para estudar a sua eficácia na terminação de um rotor simulado. A Cloroquina alongou o potencial de ação na medida em que foi aumentada a sua concentração. Em concentrações de 0,3 µM e superiores, terminou a atividade do rotor. Este é o primeiro trabalho que desenvolveu modelos matemáticos do medicamento cloroquina para estudar seu efeito sobre a terminação de um rotor. Os resultados sugerem que a cloroquina poderia ser um potente agente anti-arrítmico para o tratamento de FAp.

Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations.

Carbon monoxide (CO) that is produced in a number of different mammalian tissues is now known to have significant effects on the cardiovascular system. These include: (i) vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation of autonomic nervous system input to both the primary pacemaker and the working myocardium. Excessive CO in the environment is toxic and can initiate or mediate life threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias to an increase in the slowly inactivating, or "late" component of the Na(+) current in the mammalian heart. The main goal of this paper is to explore the basis of this pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel activity with intracellular signaling pathways in the mammalian heart. To do this, a quite well-documented mathematical model of the action potential and intracellular calcium transient in the human ventricular myocyte has been employed. In silico iterations based on this model provide a useful first step in illustrating the cellular electrophysiological consequences of CO that have been reported from mammalian heart experiments. Specifically, when the Grandi et al. model of the human ventricular action potential is utilized, and after the Na(+) and Ca(2+) currents in a single myocyte are modified based on the experimental literature, early after-depolarization (EAD) rhythm disturbances appear, and important elements of the underlying causes of these EADs are revealed/illustrated. Our modified mathematical model of the human ventricular action potential also provides a convenient digital platform for designing future experimental work and relating these changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data on CO toxicity.

In silico assessment of drug safety in human heart applied to late sodium current blockers.

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (I(NaL)) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K(+) current (I(Kr)). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of I(Kr)/I(NaL) ratio of steady-state block of drug candidates on "torsadogenic" biomarkers. The O'Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of I(NaL) and I(Kr) were evaluated. "Safety plots" were developed to illustrate the value of the specific biomarker for selected combinations of IC(50)s for I(Kr) and I(NaL) of potential drugs. The reference biomarkers at baseline changed depending on the "drug" specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of I(NaL)) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.

Simulation and mechanistic investigation of the arrhythmogenic role of the late sodium current in human heart failure.

Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na(+) current (I(NaL)) is relevant and is currently under investigation. In this study we examined the role of I(NaL) in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of I(NaL). A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human I(NaL) and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for I(NaL) in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca(2+) transient. A mechanistic investigation of intracellular Na(+) accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na(+)/K(+) pump, the Na(+)/Ca(2+) exchanger and I(NaL). The results of the simulations also showed that in failing myocytes, the enhancement of I(NaL) increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the I(NaL) prolong APD and alter Ca(2+) transient facilitating the development of early afterdepolarizations. An enhanced I(NaL) appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca(2+)](i) homeostasis of failing myocytes.

Effects of the antiarrhythmic drug dofetilide on transmural dispersion of repolarization in ventriculum. A computer modeling study.

Dofetilide is a class-III drug that inhibits the rapid component of the delayed potassium current ( I(Kr)). Experimental studies have shown that the different layers of ventricular muscle present differences in action potential duration (APD) and different responses to class III agents. It has been suggested that it contributes to APD heterogeneity in the ventricles. However, in vivo studies suggest that the strong cellular coupling reduces APD dispersion in intact heart. The aim of this paper is to study the effect of dofetilide on the action potentials (APs) in isolated ventricular cells and on APD dispersion in a strand of ventricular tissue. A mathematical model of dofetilide effects on I(Kr) has been developed and incorporated into the Luo--Rudy dynamic model of ventricular AP. Our results show that dofetilide induces in midmyocardium cells a faster time-course inhibition of I(Kr) than in endocardial or epicardial cells, and periods of instability with beat-to-beat APs variability. This behavior could favor temporal dispersion of repolarization between the different cells. The results also indicate that although dofetilide increases, the transmural gradient of APD in the ventricular wall, early afterdepolarizations (EADs) did not appear even under strong uncoupling conditions. However, reduced repolarization reserve favors the induction of EADs, even under normal coupling conditions.

Exploring the role of pH in modulating the effects of lidocaine in virtual ischemic tissue.

Lidocaine is a class I antiarrhytmic drug that blocks Na(+) channels and exists in both neutral and charged forms at a physiological pH. In this work, a mathematical model of pH and the frequency-modulated effects of lidocaine has been developed and incorporated into the Luo-Rudy model of the ventricular action potential. We studied the effects of lidocaine on Na(+) current, maximum upstroke velocity, and conduction velocity and demonstrated that a decrease of these parameters was dependent on pH, frequency, and concentration. We also tested the action of lidocaine under pathological conditions. Specifically, we investigated its effects on conduction block under acute regional ischemia. Our results in one-dimensional fiber simulations showed a reduction of the window of block in the presence of lidocaine, thereby highlighting the role of reduced conduction velocity and safe conduction. This reduction may be related to the antifibrillatory effects of the drug by hampering wavefront fragmentation. In bidimensional acute ischemic tissue, lidocaine increased the vulnerable window for reentry and exerted proarrhythmic effects. In conclusion, the present simulation study used a newly formulated model of lidocaine, which considers pH and frequency modulation, and revealed the mechanisms by which lidocaine facilitates the onset of reentries. The results of this study also help to increase our understanding of the potential antifibrillatory effects of the drug.