Field Of Cardiac Electrophysiology Research Articles

Human cardiac systems electrophysiology and arrhythmogenesis: iteration of experiment and computation.

Human cardiac electrophysiology (EP) is a unique system for computational modelling at multiple scales. Due to the complexity of the cardiac excitation sequence, coordinated activity must occur from the single channel to the entire myocardial syncytium. Thus, sophisticated computational algorithms have been developed to investigate cardiac EP at the level of ion channels, cardiomyocytes, multicellular tissues, and the whole heart. Although understanding of each functional level will ultimately be important to thoroughly understand mechanisms of physiology and disease, cardiac arrhythmias are expressly the product of cardiac tissue-containing enough cardiomyocytes to sustain a reentrant loop of activation. In addition, several properties of cardiac cellular EP, that are critical for arrhythmogenesis, are significantly altered by cell-to-cell coupling. However, relevant human cardiac EP data, upon which to develop or validate models at all scales, has been lacking. Thus, over several years, we have developed a paradigm for multiscale human heart physiology investigation and have recovered and studied over 300 human hearts. We have generated a rich experimental dataset, from which we better understand mechanisms of arrhythmia in human and can improve models of human cardiac EP. In addition, in collaboration with computational physiologists, we are developing a database for the deposition of human heart experimental data, including thorough experimental documentation. We anticipate that accessibility to this human heart dataset will further human EP computational investigations, as well as encourage greater data transparency within the field of cardiac EP.

Alterations of field potentials in isotropic cardiomyocyte cell layers induced by multiple endogenous pacemakers under normal and hypothermal conditions.

The use of autonomous contracting randomly grown cardiomyocyte monolayers cultivated on microelectrode arrays (MEAs) represents an accepted experimental setting for preclinical experimental research in the field of cardiac electrophysiology. A dominant pacemaker forces a monolayer to adhere to a regular and synchronized contraction. Randomly distributed multiple pacemakers interfere with this dominant center, resulting in more or less frequent changes of propagation direction. This study aims to characterize the impact of changing propagation directions at single electrodes of the MEA on the four intrinsic parameters of registered field potentials (FPs) FPrise, FPMIN, FPpre, and FPdur and conduction velocity (CV) under normal and hypothermal conditions. Primary cultures of chicken cardiomyocytes (n = 18) were plated directly onto MEAs and FPs were recorded in a temperature range between 37 and 29°C. The number and spatiotemporal distribution of biological and artificial pacemakers of each cell layer inside and outside of the MEA registration area were evaluated using an algorithm developed in-house. In almost every second myocardial cell layer, interfering autonomous pacemakers were detected at stable temperatures, showing random spatial distributions with similar beating rates. Additionally, a temperature-dependent change of the dominant pacemaker center was observed in n = 16 experiments. A significant spread-direction-dependent variation of CV, FPrise, FPMIN, and FPpre up to 14% could be measured between different endogenous pacemakers. In conclusion, based on our results, disregarding the spatial origin of excitation may lead to misinterpretations and erroneous conclusions of FP parameters in the verification of research hypotheses in cellular electrocardiology.

Novedades en electrofisiología cardiaca y arritmias

This article contains a review of the most important publications in the field of cardiac electrophysiology and arrhythmias that have appeared in the last year. Publications were selected because they reported important scientific developments or significant improvements in the devices or invasive techniques used for the treatment of arrhythmias.

Multiparametric Optical Mapping of the Langendorff-perfused Rabbit Heart

Optical imaging and fluorescent probes have significantly advanced research methodology in the field of cardiac electrophysiology in ways that could not have been accomplished by other approaches1. With the use of the calcium- and voltage-sensitive dyes, optical mapping allows measurement of transmembrane action potentials and calcium transients with high spatial resolution without the physical contact with the tissue. This makes measurements of the cardiac electrical activity possible under many conditions where the use of electrodes is inconvenient or impossible1. For example, optical recordings provide accurate morphological changes of membrane potential during and immediately after stimulation and defibrillation, while conventional electrode techniques suffer from stimulus-induced artifacts during and after stimuli due to electrode polarization1. The Langendorff-perfused rabbit heart is one of the most studied models of human heart physiology and pathophysiology. Many types of arrhythmias observed clinically could be recapitulated in the rabbit heart model. It was shown that wave patterns in the rabbit heart during ventricular arrhythmias, determined by effective size of the heart and the wavelength of reentry, are very similar to that in the human heart2. It was also shown that critical aspects of excitation-contraction (EC) coupling in rabbit myocardium, such as the relative contribution of sarcoplasmic reticulum (SR), is very similar to human EC coupling3. Here we present the basic procedures of optical mapping experiments in Langendorff-perfused rabbit hearts, including the Langendorff perfusion system setup, the optical mapping systems setup, the isolation and cannulation of the heart, perfusion and dye-staining of the heart, excitation-contraction uncoupling, and collection of optical signals. These methods could be also applied to the heart from species other than rabbit with adjustments to flow rates, optics, solutions, etc.Two optical mapping systems are described. The panoramic mapping system is used to map the entire epicardium of the rabbit heart4-7. This system provides a global view of the evolution of reentrant circuits during arrhythmogenesis and defibrillation, and has been used to study the mechanisms of arrhythmias and antiarrhythmia therapy8,9. The dual mapping system is used to map the action potential (AP) and calcium transient (CaT) simultaneously from the same field of view10-13. This approach has enhanced our understanding of the important role of calcium in the electrical alternans and the induction of arrhythmia14-16.

Multiparametric Optical Mapping of the Langendorff-perfused Rabbit Heart

Optical imaging and fluorescent probes have significantly advanced research methodology in the field of cardiac electrophysiology in ways that could not have been accomplished by other approaches1. With the use of the calcium- and voltage-sensitive dyes, optical mapping allows measurement of transmembrane action potentials and calcium transients with high spatial resolution without the physical contact with the tissue. This makes measurements of the cardiac electrical activity possible under many conditions where the use of electrodes is inconvenient or impossible1. For example, optical recordings provide accurate morphological changes of membrane potential during and immediately after stimulation and defibrillation, while conventional electrode techniques suffer from stimulus-induced artifacts during and after stimuli due to electrode polarization1. The Langendorff-perfused rabbit heart is one of the most studied models of human heart physiology and pathophysiology. Many types of arrhythmias observed clinically could be recapitulated in the rabbit heart model. It was shown that wave patterns in the rabbit heart during ventricular arrhythmias, determined by effective size of the heart and the wavelength of reentry, are very similar to that in the human heart2. It was also shown that critical aspects of excitation-contraction (EC) coupling in rabbit myocardium, such as the relative contribution of sarcoplasmic reticulum (SR), is very similar to human EC coupling3. Here we present the basic procedures of optical mapping experiments in Langendorff-perfused rabbit hearts, including the Langendorff perfusion system setup, the optical mapping systems setup, the isolation and cannulation of the heart, perfusion and dye-staining of the heart, excitation-contraction uncoupling, and collection of optical signals. These methods could be also applied to the heart from species other than rabbit with adjustments to flow rates, optics, solutions, etc. Two optical mapping systems are described. The panoramic mapping system is used to map the entire epicardium of the rabbit heart4-7. This system provides a global view of the evolution of reentrant circuits during arrhythmogenesis and defibrillation, and has been used to study the mechanisms of arrhythmias and antiarrhythmia therapy8,9. The dual mapping system is used to map the action potential (AP) and calcium transient (CaT) simultaneously from the same field of view10-13. This approach has enhanced our understanding of the important role of calcium in the electrical alternans and the induction of arrhythmia14-16.

Safety of Pacemaker Reuse

Background— A large disparity in medical health care is clearly evident between developed and underserved nations in the field of cardiac electrophysiology, specifically pacemaker implantation. This study aimed to assess the safety of pacemaker reuse. Methods and Results— A computerized search from January 1, 1970, to September 1, 2010, identified 18 studies with outcomes of pacemaker reuse. The primary outcome was pacemaker infection or device erosion as defined by each individual study protocol. Secondary end points were device malfunction defined as a defect in the structural or electric integrity of the pulse generator. Pooled individual patient data (n=2270) from 18 trials were included in the analysis. The proportion of patients in whom an infection developed after pacemaker reuse was 1.97% (1.15% to 3.00%). There was no significant difference in infection rate between pacemaker reuse and new device implantation (odds ratio, 1.31 [0.50 to 3.40], P =0.580). The proportion of patients in whom device malfunction developed after pacemaker reuse was 0.68% (0.27% to 1.28%). Compared with new device implantation, there was an increased risk for malfunction in the reuse group (odds ratio, 5.80 [1.93 to 17.47], P =0.002). This difference was mainly driven by abnormalities in set screws, which possibly occurred during device extraction, as well as nonspecific device “technical errors.” Conclusions— This study suggests that pacemaker reuse has an overall low rate of infection and device malfunction and may be a safe and efficacious means of treating patients in underserved nations with symptomatic bradyarrhythmias and no other method of obtaining a device. However, the results also denote a higher rate of device malfunction as compared with new device implantation. Patients with highly symptomatic conduction disease may benefit from pacemaker reuse; however, they should be closely monitored for device malfunction, especially during implantation.

Societal views of pacemaker reutilization for those with untreated symptomatic bradycardia in underserved nations

Significant healthcare disparities exist between the developed world and low and middle income countries (LMIC), specifically in the field of cardiac electrophysiology. As a result, pacemaker reutilization has been proposed as a viable option for those in LMIC and no other means of obtaining a device. Little data exist regarding the feasibility of establishing a reuse program in addition to understanding the views of society on device reutilization. This study investigated the views of funeral directors, patients with cardiac devices, and members of the general population regarding reutilization of previously implanted pacemakers. Ninety funeral directors in Michigan were surveyed regarding current practice as well as preferences for post-mortem device disposal. One hundred and fourteen patients with devices and 1,009 members of the general population were surveyed regarding post-mortem device handling. Funeral directors had an average of 21years of experience with an annual volume of 120 deceased persons per year, with a cremation rate of 35%. When asked about disposal methods of explanted devices, the majority of devices (84%) were discarded as medical waste or stored with no intended purpose, with a total of 171 devices currently in possession at the funeral homes. Eighty-nine percent of funeral directors expressed a desire to donate devices for reuse in LMIC and 10% acknowledged previous device donation. Eighty-seven percent of device patients and 71% of the general population also expressed a desire to donate devices. The results of our survey show that a large percentage of funeral directors, patients with implantable devices, and members of the general population support a pacemaker reutilization initiative. This study lends further evidence that collection of devices for reuse is feasible and that establishing a framework for regional pacemaker reutilization program is warranted. If successful, the feasibility of this model should be investigated in other parts of the country in order to alleviate the burden of untreated symptomatic bradycardia in our world.

Electrophysiology and Adult Congenital Heart Disease: Advances and Options

Although “congenital heart disease” incorporates a broad and diverse spectrum of inborn cardiac disorders, one shared feature is the propensity for cardiac arrhythmias, albeit to varying degrees. The magnitude of this issue is underscored by its high prevalence, major impact on morbidity and disability, considerable consummation of healthcare resources, and loss of life at ages well below normative population values. Moreover, with changing demographics, arrhythmias increasingly afflict the aging and growing population of survivors with congenital heart disease. Nevertheless, the field of cardiac electrophysiology has, auspiciously, greatly matured over the past 2 decades. The fruits of this progress are largely applicable to adults with congenital heart disease. This review focuses on recent advances and emerging therapeutic options that are providing safer solutions and increasing the effectiveness with which arrhythmias may be managed in adults with congenital heart disease, spanning pharmacotherapy to innovative interventions.

Stimulus Protocol Determines the Most Computationally Efficient Preconditioner for the Bidomain Equations

The efficient solution of the bidomain equations is a fundamental tool in the field of cardiac electrophysiology. When choosing a finite element discretization of the coupled system, one has to deal with the solution of a large, highly sparse system of linear equations. The conjugate gradient algorithm, along with suitable preconditioning, is the natural choice in this scenario. In this study, we identify the optimal preconditioners with respect to both stimulus protocol and mesh geometry. The results are supported by a comprehensive study of the mesh-dependence properties of several preconditioning techniques found in the literature. Our results show that when only intracellular stimulus is considered, incomplete LU factorization remains a valid choice for current cardiac geometries. However, when extracellular shocks are delivered to tissue, preconditioners that take into account the structure of the system minimize execution time and ensure mesh-independent convergence.

Genome-wide association studies in cardiac electrophysiology: Recent discoveries and implications for clinical practice

Genome-wide association studies have been increasingly used to study the genetics of complex human diseases. Within the field of cardiac electrophysiology, this technique has been applied to conditions such as atrial fibrillation, and several electrocardiographic parameters including the QT interval. While these studies have identified multiple genomic regions associated with each trait, questions remain, including the best way to explore the pathophysiology of each association and the potential for clinical utility. This review will summarize recent genome-wide association study results within cardiac electrophysiology and discuss their broader implications in basic science and clinical medicine.

Challenging cardiac electrophysiology

Challenging cardiac electrophysiology

Experimental Molecular and Stem Cell Therapies in Cardiac Electrophysiology

One of the most exciting fields in cardiovascular research today involves the possible use of stem cells, cell and gene therapies, and tissue engineering for the treatment of a variety of cardiovascular disorders. Here, we review on the possible applications of these emerging strategies in the field of cardiac electrophysiology. Initially, the elegant cell and gene therapy approaches proposed for the treatment of bradyarrhythmias are described. These gene therapy approaches are mainly focused on the generation of biological pacemakers either by altering the neurohumoral control of existing pacemaking cells (by overexpressing the beta-adrenergic receptor) or by converting quiescent cardiomyocytes into pacemaking cells by shifting the balance between diastolic repolarization and depolarization currents. An alternative approach explores the possibility of grafting pacemaking cells, which were either derived directly during the differentiation of human embryonic stem cells or engineered from mesenchymal stem cells, into the myocardium as a cell therapy strategy for biological pacemaking. We then describe the possible applications of similar strategies for the treatment of common tachyarrhythmias by overexpression of different ion channels, or their modifiers, either directly in host cardiomyocytes or ex vivo in cells that will be eventually transplanted into the heart. Next, we discuss the electrophysiological implications of cardiac stem cell therapy for heart failure. Finally, we address the obstacles, challenges, and avenues for further research required to make these novel strategies a clinical reality.

From Gene Therapy and Stem Cells to Clinical Electrophysiology

Gene therapy, cell therapy, and tissue engineering are emerging as novel experimental therapeutic paradigms for a variety of cardiovascular disorders. In the current report we will review the possible implications of these emerging technologies in the field of cardiac electrophysiology. Initially, the possible role of myocardial gene and cell therapies in creating a biological alternative to electronic pacemakers for the treatment of bradyarrhythmias will be discussed. This will be followed by a description of the possible applications of using similar strategies for the treatment of common tachyarrhythmias. Finally, the electrophysiological implications of cardiac stem cell therapy for heart failure, as well as the possible in vitro applications of stem cell technology for electrophysiological studies and drug screening, will be discussed. While these emerging strategies provide a paradigm shift from conventional treatment modalities, this field is still at its infancy and several obstacles, discussed in this review, should be overcome before any clinical breakthroughs can be expected.

Asymptomatic partial anomalous pulmonary venous return masquerading as pulmonary vein occlusion following radiofrequency ablation

Recent advances in the field of cardiac electrophysiology have resulted in the rapid growth of radiofrequency ablation for treatment of arrhythmias. Pulmonary vein stenosis or occlusion is a rare, but well described adverse outcome. Fortunately, the concomitant evolution of multislice computed tomography (CT) scanners has provided an excellent non-invasive method of monitoring for this complication. We recently encountered a case on multislice CT that initially appeared to be a pulmonary vein occlusion related to the procedure, but on further evaluation was found to be an asymptomatic case of partial anomalous pulmonary venous return.

Therapies for Ventricular Cardiac Arrhythmias

During recent years, engineers and physicists have become increasingly interested in studying the electrical activity of the heart. Despite the fact that the heart is a complex and highly nonlinear system, its electrical behavior can be studied using a variety of experimental and clinical techniques, and can be modeled mathematically using relatively simple systems of differential equations, allowing scientists to perform both real and virtual (in silico) experiments to gain insights into its physiology and pathophysiology. Although these approaches have in recent years allowed great headway to be made into understanding the dynamic behavior of the heart, cardiac arrhythmias such as ventricular fibrillation still claim the lives of hundreds of thousands of people each year in the United States alone. Bridging the gap between understanding the mechanistic bases of arrhythmias and applying such knowledge to improving therapy presents one of the greatest challenges in the field of cardiac electrophysiology. In this review, we describe the basic electrical properties and dynamic behavior of the heart and review the current state of the art in ventricular arrhythmia therapy. We also discuss some possibilities for future therapies, with the hope that such informed speculation will promote new investigations in these areas.

Computer Modeling in Cardiac Electrophysiology

The skills of a computational physicist are shown to be useful in the seemingly distant field of cardiac electrophysiology. The propagation of cardiac action potentials and their ability to form spiral waves are easily understood at a basic level when standard concepts from the theory of partial differential equations are applied. The design of computer simulations of action potential propagation is facilitated by adapting numerical concepts routinely applied by computational physicists. These concepts must be modified and combined with computer structures standard in computer science to handle the timescale and spatial scale problems unique to the action potential propagation problem. The resulting simulation shows how details of ion channel dynamics determine properties of the spiral wave, including its propagation speed, its period, its stability, and the size of the spiral core.

Digitalis and the electrocardiogram.

The various effects of digitalis upon the electrocardiogram are reviewed and grouped with regard to their clinical significance. Therapeutic or toxic actions of digitalis seem to depend on as yet poorly understood relationships to potassium metabolism. An insight into this relationship might be gained in the future in view of recent developments in the field of cardiac electrophysiology.