Optogenetic Control of Cardiac Arrhythmias

The regular, coordinated contraction of the heart muscle is orchestrated by periodic waves generated by the heart’s natural pacemaker and transmitted through the heart’s electrical conduction system. Abnormalities occurring anywhere within the cardiac electrical conduction system can disrupt the propagation of these waves. Such dis- ruptions often lead to the development of high frequency spiral waves that override normal pacemaker activity and compromise cardiac function. The occurrence of high frequency spiral waves in the heart is associated with cardiac rhythm disorders such as tachycardia and fibrillation. While tachycardia may be terminated by rapid periodic stimulation known as anti-tachycardia pacing (ATP), life-threatening ventricular fibril- lation requires a single high-voltage electric shock that resets all the activity and restore the normal heart function. However, despite the high success rate of defibrillation, it is associated with significant side effects including tissue damage, intense pain and trauma. Thus, extensive research is conducted for developing low-energy alternatives to conventional defibrillation. An example of such an alternative is the low-energy anti-fibrillation pacing (LEAP). However, the clinical application of this technique, and other evolving techniques requires a detailed understanding of the dynamics of spiral waves that occur during arrhythmias. Optogenetics is a tool, that has recently gained popularity in the cardiac research, which serves as a probe to study biological processes. It involves genetically modifying cardiac muscle cells such that they become light sensitive, and then using light of specific wavelengths to control the electrical activity of these cells. Cardiac optogenetics opens up new ways of investigating the mechanisms underlying the onset, maintenance and control of cardiac arrhythmias. In this thesis, I employ optogenetics as a tool to control the dynamics of a spiral wave, in both computer simulations and in experiments.In the first study, I use optogenetics to investigate the mechanisms underlying de- fibrillation. Analogous to the conventional single electric-shock, I apply a single globally-illuminating light pulse to a two-dimensional cardiac tissue to study how wave termination occurs during defibrillation. My studies show a characteristic transient dynamics leading to the termination of the spiral wave at low light intensities, while at high intensities, the spiral waves terminate immediately. Next, I move on to explore the use of optogenetics to study spiral wave termina- tion via drift, theoretically well-known mechanism of arrhythmia termination in the context of electrical stimulation (e.g. ATP). I show that spiral wave drift can be induced by structured illumination patterns using lights of low intensity, that result in a spatial modulation of cardiac excitability. I observe that drift occurs in the positive direction of light intensity gradient, where the spiral also rotates with a longer period. I further show how modulation of the excitability in space can be used to control the dynamics of a spiral wave, resulting in the termination of the wave by collision with the domain boundary. Based on these observations, I propose a possible mechanism of optogenetic defibrillation. In the next chapter, I use optogenetics to demonstrate control over the dynamics of the spiral waves by periodic stimulation with light of different intensities and pacing frequencies resulting in a temporal modulation of cardiac excitability. I demonstrate how the temporal modulation of excitability leads to efficient termination of arrhythmia. In addition, I use computer simulations to identify mechanisms responsible for arrhyth- mia termination for sub- and supra-threshold light intensities. My numerical results are supported by experimental studies on intact hearts, extracted from transgenic mice. Finally, I demonstrate that cardiac optogenetics not only allows control of excita- tion waves, but also by generating new waves through the induction of wave breaks. We demonstrate the effects of high sub-threshold illumination on the morphology of the propagating wave, leading to the creation of new excitation windows in space that can serve as potential sites for re-entry initiation. In summary, this thesis investigates several approaches to control arrhythmia dy- namics using optogenetics. The experimental and numerical results demonstrate the potential of feedback-induced resonant pacing as a low-energy method to control arrhythmia.2022-01-1

Sparks and waves in a stochastic fire-diffuse-fire model of Ca2+

Calcium ions are an important second messenger in living cells. Indeed calcium signals in the form of waves have been the subject of much recent experimental interest. It is now well established that these waves are composed of elementary stochastic release events (calcium puffs) from spatially localized calcium stores. Here we develop a computationally inexpensive model of calcium release based upon a stochastic generalization of the Fire-Diffuse-Fire (FDF) threshold model. Our model retains the discrete nature of calcium stores, but also incorporates a notion of release probability via the introduction of threshold noise. Numerical simulations of the model illustrate that stochastic calcium release leads to the spontaneous production of calcium sparks that may merge to form saltatory waves. In the parameter regime where deterministic waves exist it is possible to identify a critical level of noise defining a non-equilibrium phase-transition between propagating and abortive structures. A statistical analysis shows that this transition is the same as for models in the directed percolation universality class. Moreover, in the regime where no initial structure can survive deterministically, threshold noise is shown to generate a form of array enhanced coherence resonance whereby all calcium stores release periodically and simultaneously

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

Effect of myocyte-fibroblast coupling on the onset of pathological dynamics in a model of ventricular tissue

Managing lethal cardiac arrhythmias is one of the biggest challenges in modern cardiology, and hence it is very important to understand the factors underlying such arrhythmias. While early afterdepolarizations (EAD) of cardiac cells is known to be one such arrhythmogenic factor, the mechanisms underlying the emergence of tissue level arrhythmias from cellular level EADs is not fully understood. Another known arrhythmogenic condition is fibrosis of cardiac tissue that occurs both due to aging and in many types of heart diseases. In this paper we describe the results of a systematic insilico study, using the TNNP model of human cardiac cells and MacCannell model for (myo) fibroblasts, on the possible effects of diffuse fibrosis on arrhythmias occurring via EADs. We find that depending on the resting potential of fibroblasts (VFR), M-F coupling can either increase or decrease the region of parameters showing EADs. Fibrosis increases the probability of occurrence of arrhythmias after a single focal stimulation and this effect increases with the strength of the M-F coupling. While in our simulations, arrhythmias occur due to fibrosis induced ectopic activity, we do not observe any specific fibrotic pattern that promotes the occurrence of these ectopic sources

A comparative study fourth order runge kutta-tvd Scheme and fluent software case of inlet flow problems

Inlet as part of aircraft engine plays important role in controlling the rate of airflow entering to the engine. The shape of inlet has to be designed in such away to make the rate of airflow does not change too much with angle of attack and also not much pressure losses at the time, the airflow entering to the compressor section. It is therefore understanding on the flow pattern inside the inlet is important. The present work presents on the use of the Fourth Order Runge Kutta – Harten Yee TVD scheme for the flow analysis inside inlet. The flow is assumed as an inviscid quasi two dimensional compressible flow. As an initial stage of computer code development, here uses three generic inlet models. The first inlet model to allow the problem in hand solved as the case of inlet with expansion wave case. The second inlet model will relate to the case of expansion compression wave. The last inlet model concerns with the inlet which produce series of weak shock wave and end up with a normal shock wave. The comparison result for the same test case with Fluent Software [1, 2] indicates that the developed computer code based on the Fourth Order Runge Kutta – Harten – Yee TVD scheme are very close to each other. However for complex inlet geometry, the problem is in the way how to provide an appropriate mesh model

Receptors, sparks and waves in a fire-diffuse-fire framework for calcium release

Calcium ions are an important second messenger in living cells. Indeed calcium signals in the form of waves have been the subject of much recent experimental interest. It is now well established that these waves are composed of elementary stochastic release events (calcium puffs or sparks) from spatially localised calcium stores. The aim of this paper is to analyse how the stochastic nature of individual receptors within these stores combines to create stochastic behaviour on long timescales that may ultimately lead to waves of activity in a spatially extended cell model. Techniques from asymptotic analysis and stochastic phase-plane analysis are used to show that a large cluster of receptor channels leads to a release probability with a sigmoidal dependence on calcium density. This release probability is incorporated into a computationally inexpensive model of calcium release based upon a stochastic generalization of the Fire-Diffuse-Fire (FDF) threshold model. Numerical simulations of the model in one and two dimensions (with stores arranged on both regular and disordered lattices) illustrate that stochastic calcium release leads to the spontaneous production of calcium sparks that may merge to form saltatory waves. Illustrations of spreading circular waves, spirals and more irregular waves are presented. Furthermore, receptor noise is shown to generate a form of array enhanced coherence resonance whereby all calcium stores release periodically and simultaneously

A comparative study of early afterdepolarization-mediated fibrillation in two mathematical models for human ventricular cells

Early afterdepolarizations (EADs), which are abnormal oscillations of the membrane potential at the plateau phase of an action potential, are implicated in the development of cardiac arrhythmias like Torsade de Pointes. We carry out extensive numerical simulations of the TP06 and ORd mathematical models for human ventricular cells with EADs. We investigate the different regimes in both these models, namely, the parameter regimes where they exhibit (1) a normal action potential (AP) with no EADs, (2) an AP with EADs, and (3) an AP with EADs that does not go back to the resting potential. We also study the dependence of EADs on the rate of at which we pace a cell, with the specific goal of elucidating EADs that are induced by slow or fast rate pacing. In our simulations in two-and three-dimensional domains, in the presence of EADs, we find the following wave types: (A) waves driven by the fast sodium current and the L-type calcium current (Na-Ca-mediated waves); (B) waves driven only by the L-type calcium current (Ca-mediated waves); (C) phase waves, which are pseudo-travelling waves. Furthermore, we compare the wave patterns of the various wave-types (Na-Ca-mediated, Ca-mediated, and phase waves) in both these models. We find that the two models produce qualitatively similar results in terms of exhibiting Na-Ca-mediated wave patterns that are more chaotic than those for the Ca-mediated and phase waves. However, there are quantitative differences in the wave patterns of each wave type. The Na-Ca-mediated waves in the ORd model show short-lived spirals but the TP06 model does not. The TP06 model supports more Ca-mediated spirals than those in the ORd model, and the TP06 model exhibits more phase-wave patterns than does the ORd model