New Paradigm of Defibrillation: Towards Painless Therapy

Sudden cardiac death: SCD) causes approximately 300,000 - 400,000 deaths a year in the United States. It usually starts as ventricular tachycardia: VT) and then degenerates into ventricular fibrillation: VF). Implantable cardioverter defibrillator: ICD) therapy is the only reliable treatment of VT/VF and has been shown to effectively reduce mortality by many clinical trials. However, high-voltage ICD shocks could result in myocardial dysfunction and damage. The majority of patients receiving ICD therapy have a history of coronary disease; their hearts develop myocardium infarction, which could provide a substrate for reentrant tachy-arrhythmias. Other than lethal ventricular tachycardia, atrial fibrillation: AF) became the most common arrhythmia by affecting 2.2 to 5.6 millions of Americans. The complications of AF include an increased rate of mortality, heart failure, stroke, etc. In this dissertation, we explore mechanisms of sustained ventricular and atrial tachyarrhythmias and the mechanisms of defibrillation using the conventional high-voltage single shock. Through the use of novel fluorescent optical mapping techniques and several animal models of ventricular and atrial arrhythmias, we develop and validate several novel low-voltage defibrillation therapies for atrial and ventricular arrhythmias. Several important previous studies on mechanisms of arrhythmia maintenance and termination using mathematical and experimental models are overviewed in Chapter 2. A study on multiple monophasic shocks improving electrotherapy of ventricular tachycardia in rabbit model of chronic infarction is presented in Chapter 3. Ventricular arrhythmias and low-voltage defibrillation therapy are studied in a more clinically-relevent in vivo canine model of healing myocardial infarction in Chapter 4. Finally, Chapter 5 presents a novel multi-stage low-energy defibrillation therapy for atrial fibrillation in in vivo canine hearts

A Mechanistically Guided Approach to Treatment of Multi-Wavelet Reentry: Experiments in a Computational Model of Cardiac Propagation

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States today. However, treatment options remain limited despite the enormous magnitude of both AF prevalence and the associated economic cost. Of those treatment options that are available, ablation-based interventional methods have demonstrated the highest rates of long-term cure. Unfortunately, these methods have substantially lower efficacy in patients with heavier burdens of disease, thus leaving the most affected individuals with the least hope for successful treatment. The focus of this research is to develop a mechanistically guided approach towards the treatment of multi-wavelet reentry (MWR), one of the primary drivers of AF. For this purpose, we use a computational model of electrical propagation in cardiac tissue to simulate both episodes of fibrillatory activity and the ablative treatment thereof. We demonstrate that the probability of forming the reentrant circuits necessary for continuous electrical activity is a function of the shape and size of a tissue as well as its underlying cellular properties. Ablation at tissue sites with high probability of circuit formation more efficiently reduces the overall duration of fibrillatory episodes than ablation at sites with low probability. We then propose and validate in silico a parameter-based metric for predicting the propensity of an individual tissue to support fibrillation, which we term the fibrillogenicity index. Using this metric, we develop an algorithm for prospectively determining optimized, tissue-specific ablation patterns. Finally, we examine the relationship between multi-wavelet reentry and focal drivers, and demonstrate that MWR and fibrillatory conduction exist along a continuum. We examine the complex interplay between functional and structural substrates within fibrillating tissue and define the mechanisms by which they promote the perpetuation of AF. These findings present a novel theoretical framework for understanding treatment of multi-wavelet reentry driven AF and provide a set of testable predictions that can serve to guide the design of future experimental studies aimed at advancing the rational design of patient-specific ablation sets for treating AF

Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating

Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias. Here we present proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. For the heart, its realization involves the integration of ion channels with newly designed gating properties into cardiomyocytes. This allows cardiac tissue to i) discriminate between normal rhythm and arrhythmia based on frequency-dependent gating and ii) generate an ionic current for termination of the detected arrhythmia. We show in silico, that for both human atrial and ventricular arrhythmias, activation of these channels leads to rapid and repeated restoration of normal excitation rhythm. Experimental validation is provided by injecting the designed channel current for arrhythmia termination in human atrial myocytes using dynamic clamp

Rotor termination is critically dependent on kinetic properties of I Kur inhibitors in an In Silico model of chronic atrial fibrillation

Inhibition of the atrial ultra-rapid delayed rectifier potassium current (I Kur) represents a promising therapeutic strategy in the therapy of atrial fibrillation. However, experimental and clinical data on the antiarrhythmic efficacy remain controversial. We tested the hypothesis that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of channel blockade. A mathematical description of I Kur blockade was introduced into Courtemanche-Ramirez-Nattel models of normal and remodeled atrial electrophysiology. Effects of five model compounds with different kinetic properties were analyzed. Although a reduction of dominant frequencies could be observed in two dimensional tissue simulations for all compounds, a reduction of spiral wave activity could be only be detected in two cases. We found that an increase of the percent area of refractory tissue due to a prolongation of the wavelength seems to be particularly important. By automatic tracking of spiral tip movement we find that increased refractoriness resulted in rotor extinction caused by an increased spiral-tip meandering. We show that antiarrhythmic effects of I Kur inhibitors are dependent on kinetic properties of blockade. We find that an increase of the percent area of refractory tissue is the underlying mechanism for an increased spiral-tip meandering, resulting in the extinction of re-entrant circuits

Studies on the dynamics of chaotic multi-wavelet reentrant propagation using a hybrid cellular automaton model of excitable tissue

There is a compelling body of evidence implicating continuous propagation (reentry) sustained by multiple meandering wavelets in the pathology of advanced human atrial fibrillation (AF). This forms the basis for many current therapies such as the Cox MAZE procedure and its derivatives, which aim to create non-conducting lesions in order to "transect" these circuits before they form. Nevertheless, our ability to successfully treat persistent and permanent AF using catheter ablation remains inadequate due to current limitations of clinical mapping technology as well as an incomplete understanding of how to place lesions in order to maximize circuit transection and, more importantly, minimize AF burden. Here, we used a hybrid cellular automaton model to study the dynamics of chaotic, multi-wavelet reentry (MWR) in excitable tissue. First, we used reentry as an exemplar to investigate a hysteretic disease mechanism in a multistable nonlinear system. We found that certain interactions with the environment can cause persistent changes to system behavior without altering its structure or properties, thus leading to a disconnect between clinical symptoms and the underlying state of disease. Second, we developed a novel analytical method to characterize the spatiotemporal dynamics of MWR. We identified a heterogeneous spatial distribution of reentrant pathways that correlated with the spatial distribution of cell activation frequencies. Third, we investigated the impact of topological and geometrical substrate alterations on the dynamics of MWR. We demonstrated a multi-phasic relationship between obstacle size and the fate of individual episodes. Notably, for a narrow range of sizes, obstacles appeared to play an active role in rapidly converting MWR to stable structural reentry. Our studies indicate that reentrant-pathway distributions are non-uniform in heterogeneous media (such as the atrial myocardium) and suggest a clinically measurable correlate for identifying regions of high circuit density, supporting the feasibility of patient-specific targeted ablation. Moreover, we have elucidated the key mechanisms of interaction between focal obstacles and MWR, which has implications for the use of spot ablation to treat AF as some recent studies have suggested

Multiscale Modeling of Cardiac Electrophysiology: Adaptation to Atrial and Ventricular Rhythm Disorders and Pharmacological Treatment

Multiscale modeling of cardiac electrophysiology helps to better understand the underlying mechanisms of atrial fibrillation, acute cardiac ischemia and pharmacological treatment. For this purpose, measurement data reflecting these conditions have to be integrated into models of cardiac electrophysiology. Several methods for this model adaptation are introduced in this thesis. The resulting effects are investigated in multiscale simulations ranging from the ion channel up to the body surface

Dynamical anchoring of distant Arrhythmia Sources by Fibrotic Regions via Restructuring of the Activation Pattern

Rotors are functional reentry sources identified in clinically relevant cardiac arrhythmias, such as ventricular and atrial fibrillation. Ablation targeting rotor sites has resulted in arrhythmia termination. Recent clinical, experimental and modelling studies demonstrate that rotors are often anchored around fibrotic scars or regions with increased fibrosis. However the mechanisms leading to abundance of rotors at these locations are not clear. The current study explores the hypothesis whether fibrotic scars just serve as anchoring sites for the rotors or whether there are other active processes which drive the rotors to these fibrotic regions. Rotors were induced at different distances from fibrotic scars of various sizes and degree of fibrosis. Simulations were performed in a 2D model of human ventricular tissue and in a patient-specific model of the left ventricle of a patient with remote myocardial infarction. In both the 2D and the patient-specific model we found that without fibrotic scars, the rotors were stable at the site of their initiation. However, in the presence of a scar, rotors were eventually dynamically anchored from large distances by the fibrotic scar via a process of dynamical reorganization of the excitation pattern. This process coalesces with a change from polymorphic to monomorphic ventricular tachycardia.Comment: 16 pages, 7 figure

Nonlinear physics of electrical wave propagation in the heart: a review

The beating of the heart is a synchronized contraction of muscle cells (myocytes) that are triggered by a periodic sequence of electrical waves (action potentials) originating in the sino-atrial node and propagating over the atria and the ventricles. Cardiac arrhythmias like atrial and ventricular fibrillation (AF,VF) or ventricular tachycardia (VT) are caused by disruptions and instabilities of these electrical excitations, that lead to the emergence of rotating waves (VT) and turbulent wave patterns (AF,VF). Numerous simulation and experimental studies during the last 20 years have addressed these topics. In this review we focus on the nonlinear dynamics of wave propagation in the heart with an emphasis on the theory of pulses, spirals and scroll waves and their instabilities in excitable media and their application to cardiac modeling. After an introduction into electrophysiological models for action potential propagation, the modeling and analysis of spatiotemporal alternans, spiral and scroll meandering, spiral breakup and scroll wave instabilities like negative line tension and sproing are reviewed in depth and discussed with emphasis on their impact in cardiac arrhythmias.Peer ReviewedPreprin

Cardiac electrophysiology and mechanoelectric feedback : modeling and simulation

Cardiac arrhythmia such as atrial and ventricular fibrillation are characterized by rapid and irregular electrical activity, which may lead to asynchronous contraction and a reduced pump function. Besides experimental and clinical studies, computer simulations are frequently applied to obtain insight in the onset and perpetuation of cardiac arrhythmia. In existing models, the excitable tissue is often modeled as a continuous two-phase medium, representing the intracellular and interstitial domains, respectively. A possible drawback of continuous models is the lack of flexibility when modeling discontinuities in the cardiac tissue. We introduce a discrete bidomain model in which the cardiac tissue is subdivided in segments, each representing a small number of cardiac cells. Active membrane behavior as well as intracellular coupling and interstitial currents are described by this model. Compared with the well-known continuous bidomain equations, our Cellular Bidomain Model is better aimed at modeling the structure of cardiac tissue, in particular anisotropy, myofibers, fibrosis, and gap junction remodeling. An important aspect of our model is the strong coupling between cardiac electrophysiology and cardiomechanics. Mechanical behavior of a single segment is modeled by a contractile element, a series elastic element, and a parallel elastic element. Active force generated by the sarcomeres is represented by the contractile element together with the series elastic element. The parallel elastic element describes mechanical behavior when the segment is not electrically stimulated. Contractile force is related to the intracellular calcium concentration, the sarcomere length, and the velocity of sarcomere shortening. By incorporating the influence of mechanical deformation on electrophysiology, mechanoelectric feedback can be studied. In our model, we consider the immediate influence of stretch on the action potential by modeling a stretch-activated current. Furthermore, we consider the adap- tation of ionic membrane currents triggered by changes in mechanical load. The strong coupling between cardiac electrophysiology and cardiac mechanics is a unique property of our model, which is reflected by its application to obtain more insight in the cause and consequences of mechanical feedback on cardiac electrophysiology. In this thesis, we apply the Cellular Bidomain Model in five different simulation studies to cardiac electrophysiology and mechanoelectric feedback. In the first study, the effect of field stimulation on virtual electrode polarization is studied in uniform, decoupled, and nonuniform cardiac tissue. Field stimulation applied on nonuniform tissue results in more virtual electrodes compared with uniform tissue. Spiral waves can be terminated in decoupled tissue, but not in uniform, homogeneous tissue. By gradually increasing local differences in intracellular conductivities, the amount and spread of virtual electrodes increases and spiral waves can be terminated. We conclude that the clinical success of defibrillation may be explained by intracellular decoupling and spatial heterogeneity present in normal and in pathological cardiac tissue. In the second study, the role of the hyperpolarization-activated inward current If is investigated on impulse propagation in normal and in pathological tissue. The effect of diffuse fibrosis and gap junction remodeling is simulated by reducing cellular coupling nonuniformly. As expected, the conduction velocity decreases when cellular coupling is reduced. In the presence of If, the conduction velocity increases both in normal and in pathological tissue. In our simulations, ectopic activity is present in regions with high expression of If and is facilitated by cellular uncoupling. We also found that an increased If may facilitate propagation of the action potential. Hence, If may prevent conduction slowing and block. Overexpression of If may lead to ectopic activity, especially when cellular coupling is reduced under pathological conditions. In the third study, the influence of the stretch-activated current Isac is investigated on impulse propagation in cardiac fibers composed of segments that are electrically and mechanically coupled. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between conduction velocity and Isac under stretch. Conduction slowing and block are related to the amount of stretch and are enhanced by contraction of early-activated segments. Our observations are in agreement with experimental results and explain the large differences in intra-atrial conduction, as well as the increased inducibility of atrial fibrillation in acutely dilated atria. In the fourth study, we investigate the hypothesis that electrical remodeling is triggered by changes in mechanical work. Stroke work is determined for each segment by simulating the cardiac cycle. Electrical remodeling is simulated by adapting the L-type Ca2+ current ICa,L such that a homogeneous distribution of stroke work is obtained. With electrical remodeling, a more homogeneous shortening of the fiber is obtained, while heterogeneity in APD increases and the repolarization wave reverses. These results are in agreement with experimentally observed distributions of strain and APD and indicate that electrical remodeling leads to more homogeneous shortening during ejection. In the fifth study, we investigate the effect of stretch on the vulnerability to AF. The human atria are represented by a triangular mesh obtained from MRI data. To model acute dilatation, overall stretch is applied to the atria. In the presence of Isac, the membrane potential depolarizes, which causes inactivation of the sodium channels and results in conduction slowing or block. Inducibility of AF increases under stretch, which is explained by an increased dispersion in refractory period, conduction slowing, and local conduction block. Our observations explain the large differences in intra-atrial conduction measured in experiments and provide insight in the vulnerability to AF in dilated atria. In conclusion, our model is well-suited to describe cardiac electrophysiology and mechanoelectric feedback. For future applications, the model may be improved by taking into account new insights from cellular physiology, a more accurate geometry, and hemodynamics

Circ Res

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans. The mechanisms that govern AF initiation and persistence are highly complex, of dynamic nature, and involve interactions across multiple temporal and spatial scales in the atria. This article aims to review the mathematical modeling and computer simulation approaches to understanding AF mechanisms and aiding in its management. Various atrial modeling approaches are presented, with descriptions of the methodological basis and advancements in both lower-dimensional and realistic geometry models. A review of the most significant mechanistic insights made by atrial simulations is provided. The article showcases the contributions that atrial modeling and simulation have made not only to our understanding of the pathophysiology of atrial arrhythmias, but also to the development of AF management approaches. A summary of the future developments envisioned for the field of atrial simulation and modeling is also presented. The review contends that computational models of the atria assembled with data from clinical imaging modalities that incorporate electrophysiological and structural remodeling could become a first line of screening for new AF therapies and approaches, new diagnostic developments, and new methods for arrhythmia prevention.DP1 HL123271/HL/NHLBI NIH HHS/United StatesDP1HL123271/DP/NCCDPHP CDC HHS/United States2015-04-25T00:00:00Z24763468PMC4043630vault:242