Browsing by Author "Nygren, Anders"

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    Approaches to the Calibration of Single-Cell Cardiac Models Based on Determinants of Multi-Cellular Electrical Interactions
    (2021-03-17) Pouranbarani, Elnaz; Nygren, Anders; Rose, Robert; Behjat, Laleh; Di Martino, Elena; Dubljevic, Stevan
    Cardiac single-cell models are often used as building blocks for tissue simulation. Cellular models can successfully reproduce the expected behaviour at the tissue scale, providing that a single cell is accurately modeled. One of the imprecisions of conventional cellular modeling, evident mainly when the models are used at the tissue level, stems from only considering some cellular properties (e.g., action potential (AP) shape) and ignoring properties that reflect interconnections of the cells in the calibration/optimization process. This can result in inaccurate modeling of intercellular electrical communications. Computational models are used in a well-known Safety Pharmacology paradigm (i.e., the Comprehensive in Vitro Proarrhythmia Assay), the goal of which is to evaluate drug effects on the occurrence of proarrhythmia. So, accurate characterization of cellular models’ properties is of great importance. In this thesis, a cellular multi-objective optimization framework is proposed to consider the fitness of membrane resistance (Rm) (i.e., an indicator of cellular interconnection) in addition to AP as an additional optimization objective. As Rm depends on the transmembrane voltage (Vm) and exhibits singularities for some specific values of Vm, analyses are conducted to carefully select the regions of interest for the proper characterization of Rm. To verify the efficacy of the proposed problem formulation, case studies and comparisons are carried out using human cardiac ventricular models. Afterward, the performance of the framework proposed in the previous step is analyzed at the tissue-level using various tissue configurations: source-sink configuration, Purkinje-myocardium configuration, and transmural APD heterogeneity configuration. The comprehensive statistical analyses suggest that considering Rm in the calibration procedure results in a significant reduction of errors in cardiac tissue simulations. In the subsequent step, due to the variations among tissue simulations, it is proposed to include more essential properties to constrain the calibration problem. To achieve this, a machine learning-based approach is presented. The numerical results show that the proposed method efficiently estimates the base model’s parameters. Therefore, using a calibrated model as building blocks of tissue simulation yields accurate replication of reference behaviour at the tissue scale.
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    Beyond Service Learning: Towards an Understanding of Engineering Student Development of Social Responsibility
    (2018-09-26) Jatana, Lauren Shawna; Eggermont, Marjan J.; Brennan, Robert William; Li, Simon; Nygren, Anders
    More than ever, engineering students must be prepared for social responsibility. The 20th-century saw unprecedented social and technical advancement, leading to population growth and depleting natural resources. As a result, engineering educators have been called upon to prepare students for these professional social responsibilities. However, social responsibility is more discretionary and interpretive than legal and ethical responsibilities, and educators lack clarity on what exactly social responsibility entails and how to design effective learning experiences for it. This thesis explores the relationship between student participation in various engineering learning experiences and social responsibility. Results of this study show that fourth- year students were likely to have higher social responsibility measures than first-year students, especially in a professional capacity. Participation in certain learning experiences corresponded to increased social responsibility measures, while others did not. Lastly, the results show that social responsibility measures could be correlated with three professional graduate attributes.
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    Cardiac impulse propagation in diabetic heart: response to oxidative stress and ischemia
    (2011) Rahnema Naserabad, Parisa; Nygren, Anders; Shimoni, Yakhin
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    Computational Modeling of Electrical Cell-to-cell Interactions in Cardiac Tissue: Applications to Model Parameter Selection and Pacemaker Function
    (2017) Kaur, Jaspreet; Vigmond, Edward; Nygren, Anders; Di Martino, Elena; Hu, Yaoping; Murari, Kartikeya; Clancy, Colleen
    Cell-to-cell interactions are important in determining the electrophysiological behavior of cardiac tissue. In this research, computer modeling is used to investigate the importance of these interactions in two different contexts: 1) how to adjust parameters in single cell models to accurately reproduce tissue behavior, and 2) determining requirements for successful conduction at the interface between different tissue types, specifically from the sinoatrial node (SAN) to the atrium. Membrane resistance (Rm), the inverse of the slope of the current-voltage (I/V) relationship for a cardiac myocyte, is an important determinant of electrical cell-to-cell interactions. Experimentally, Rm can be measured by applying a small current and measuring the resulting change in membrane voltage. To investigate the importance of Rm, a multi-objective genetic algorithm approach was developed for enhancing the fitting of action potentials (APs) in single cell models. Rm was fit at several points during the AP along with AP morphology. The results demonstrate that including Rm as a fitting criterion yields improved convergence, reduced variability in parameter estimates, and improved robustness, while specifically improving the ability of the model to reproduce tissue behavior. Bioengineered pacemakers are cellular constructs intended to replace the SAN pacemaker function. The interface between the SAN and atrium appears to have features designed to facilitate conduction. Depending on the species, these features involve gradual transitions (gradients) in ion channel densities and coupling conductance, or insulating boundaries with conduction at discrete exit points only. We used simulations to determine the importance of each of these features, with the aim to provide guidance to future development of bioengineered pacemakers. We found that gradients in ionic conductance (specifically ICaL) are required in rabbit SAN. There is narrow range of coupling for which the SAN is able to propagate towards atrium without coupling gradients. In canine SAN, these gradients support conduction. However, gradients are not required, provided conduction from SAN to atrium is restricted to discrete exit points. This suggests two possible strategies for successful conduction at the interface between a bioengineered pacemaker and the atrium: 1) engineer the construct to have appropriate ionic current and intercellular coupling gradients, or 2) functionally insulate a homogeneous construct from the atrium with conduction only at discrete points.
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    Computer modeling of mouse atrial cell electrophysiology
    (2009) Chockalingam, Priya; Nygren, Anders
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    Contribution of the Purkinje System in Initiation and Maintenance of Arrhythmias
    (2016) Behradfar, Elham; Vigmond, Edward J.; Nygren, Anders; Fear, Elise C.; Berenfeld, Omer; Davidsen, Jörn
    The Purkinje system is the conduction network of the heart that facilitates coordinated ventricular contraction and couples to the myocardium at discrete sites called Purkinje-Myocyte Junctions (PMJs). Fine and intricate geometry of the Purkinje system have confined experimental observations, therefore density and distribution of PMJs and Purkinje system contribution during cardiac arrhythmia are unclear. This thesis presents a detailed computer simulation study that highlights the role of the Purkinje system and its interaction with ventricles in arrhythmogenesis and maintenance. Firstly, simulations were performed on a model of rabbit ventricles to explore Purkinje system contributions during ventricular fibrillation. A fractal method for growing the Purkinje system was implemented to allow construction of anatomically realistic Purkinje network and investigation of PMJ density. The role of the Purkinje system in maintaining the arrhythmia was assessed by analyzing reentry dynamics. Results showed that the activation pattern at PMJs had little consistency over time during functional reentry, and a Purkinje system with a higher PMJ density contributed more to reentrant arrhythmia; however, the overall dynamics of sustained reentry did not appear to be significantly affected by Purkinje system complexity and coupling strengths at PMJs. Secondly, the realistic model of the Purkinje system was used to investigate mechanisms through which reduced myocardial coupling, induced by ischemia, modify the interaction between the Purkinje system and ventricular tissue, and affect ventricular excitation pattern. Experimental and modeling results suggest that ischemia-induced closing of gap junctions activates normally quiescent PMJs due to reduced source-sink mismatch and as a result, increased the complexity of activation. Modeling results indicated that a higher number of functional PMJs can speed activation of tissue and compensate for effects of uncoupling in slowing activation of the ventricles. Finally, effects of a potential antiarrhythmic drug, dantrolene, on suppressing delayed afterdepolarizations (DADs) due to Calcium overload were modeled. In ventricular model, rapid pacing promoted triggered activity but only those arising in the Purkinje fibers could generate action potential that propagated throughout the myocardium. According to modeling results, dantrolene could eliminate DAD at the Purkinje level by blocking channels that are only present in the Purkinje system.
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    Correction of Motion Artifacts in Whole Heart Optical Mapping Data Using Ratiometry and Image Processing Techniques
    (2015-12-22) Rodriguez Ramirez, Marcela Patricia; Nygren, Anders; Lichti, Derek; Murari, Kartikeya; Duncan, Neil; Oudit, Gavin
    Cardiac optical mapping is a powerful tool to understand the electrophysiological mechanisms responsible for normal and abnormal cardiac rhythm. However, motion artifacts contained in the optical action potentials (APs) represent a major drawback of the technique. The calculation of electrophysiological parameters of interest such as action potential duration (APD) is challenged by the presence of motion artifacts. The use of chemical motion blockers is currently a preferable method to control motion artifacts, however these may affect the cardiac electrophysiology and consensus regarding their effects has not been reached. This thesis presents several key developments in techniques for motion artifact correction. Weighted ratiometry was implemented aiming to reduce motion artifacts in dual wavelength recordings. This thesis reports differences in shape and amplitude between motion artifacts contained in corresponding APs at both wavelengths. A new mathematical representation for motion artifacts is also presented to model such differences. Gross motion artifacts due to misalignment of the preparation with the imaging sensor across time are the result of the mechanical contraction of the heart. Landmark-based image registration is introduced to correct for such artifacts. It was concluded that the use of scale invariant feature transform (SIFT) is preferable for the datasets presented among the techniques evaluated for motion estimation. Several landmark-based non-rigid registration methods are studied in this thesis and their performance compared; coherence point drift (CPD) algorithms performed better for this application. Image registration resulted in good correction of gross motion artifacts, however artifacts with other origins must be handled separately. The combination of weighted ratiometry and landmark-based non-rigid registration is also evaluated as a composite method to further reduce artifacts that the techniques were not able to correct individually. The technique produced good correction and APDs calculated from the corrected datasets present low error values compared to a gold standard. APD modulation with 4-Aminopyridine served as a tool to corroborate that the combination of weighted ratiometry and image registration is able to reduce motion artifacts in APs to the point where APD can be calculated and the modulation of APD quantified.
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    Development of a CDIO Framework for Teacher Training in Computational Thinking
    (2017) Hladik, Stephanie; Behjat, Laleh; Nygren, Anders; Moshirpour, Mohammad; Hugo, Ron; Haque, Anis
    Studies have shown that though there is a recent push to include computational thinking and coding in elementary schools, many elementary school teachers have no background in the subject and would require training to effectively teach computational thinking to their students. In this thesis, the development of a framework to train elementary school teachers and students in computational thinking is presented. It is based on a framework for engineering education, and modifies that framework to design and implement creative, cross-curricular activities to teach computational thinking and engineering concepts for students in grades K-6. The activities are also used in a professional development workshop to train teachers in these skills. These activities have positive impacts on perceptions of computational thinking for both elementary school teachers and their students, as evaluated by surveys and interview responses. As well, teachers felt more confident in their ability to implement similar activities in their classrooms.
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    Impacts of Aging and Hypertension on Fibrosis and Electrical Conduction in the Sinoatrial Node and Atria
    (2020-07-14) Mackasey, Martin; Rose, Robert Alan; Fedak, Paul; Nygren, Anders
    Sinoatrial node (SAN) and atrial fibrosis are major mediators of sinus node dysfunction (SND) and atrial fibrillation (AF), respectively. Both frequently co-exist in pathological states involving enhanced fibrotic remodeling. Aging and hypertension are characterized by electrical and structural remodeling and have been identified as important risk factors for the development of SND and AF. However, the underlying mechanisms facilitating these processes are incompletely understood. Natriuretic peptides (NPs) are a family of cardioprotective hormones that act partially through activation of the natriuretic peptide receptor type-C (NPR-C); although, its capacity to regulate cardiac remodeling is poorly understood. The studies presented examine the role of SAN and atrial fibrosis in regulating electrical conduction using two models associated with adverse remodeling: aging and Ang II-mediated hypertension. Aging studies also investigated the utility of assessing frailty to gain further insight into age-associated mechanisms of structural remodeling and arrhythmogenesis. Accordingly, aged and hypertensive mice exhibited enhanced SAN and atrial fibrosis as assessed by picrosirius red staining. This impacted electrical conduction as assessed by optical mapping experiments and promoted arrhythmogenesis. Frailty scores were correlated with several aspects of the remodeling process, including gene expression changes, indicating the potential for frailty score to provide additional insight into cellular and sub-cellular mechanisms. Aged and hypertensive mice exhibited distinct gene expression alterations in regulators of the cardiac extracellular matrix including collagens, transforming growth factor β1 (TGFβ1), lysyl oxidase (LOX), matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs). In studies examining the role of NPR-C in Ang II-mediated hypertension, NPR-C-/- mice displayed substantially worse outcomes with respect to SAN and atrial fibrosis as well as electrical impairments. These alterations were associated with changes in ECM-related gene expression. Conversely, a selective NPR-C agonist cANF potently prevented Ang II-mediated fibrosis and electrical impairments. However, these changes were generally not accompanied by ECM-related gene expression alterations. Taken together, these results demonstrate a crucial role for adverse fibrotic remodeling in influencing electrical conduction and arrhythmogenesis in the SAN and atria. Additionally, these studies show that NPR-C signaling exhibits potent anti-fibrotic effects that could be utilized for future therapeutic approaches in hypertension.
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    Integration of Innovation Techniques for Electronics Design and Education
    (2018-09-21) Marasco, Emily Ann; Behjat, Laleh; Rosehart, William Daniel; Nygren, Anders; Eggermont, Marjan J.; Kelly, Robert; Taylor, Lynn; McCahan, Susan
    Creative ability and innovative design have become essential skills for engineers as industries continue to face increasing technical challenges. Current engineering education initiatives focus on creativity within introductory and senior design courses, with limited work related to creative ability development within technical engineering courses. This thesis presents three contributions for integrating creative thinking and development in technical electrical and computer engineering education. The first contribution is the development of a course design architecture for planning courses with integrated creative learning outcomes. The second contribution is the development of a formalized project structure for designing technical projects that develop creative skills. The third contribution is the design of a hierarchy for developing creative thinking through divergent and convergent thinking processes. The developed approaches integrate concepts from engineering design processes, project management, entrepreneurship, arts education techniques, and game-based learning to create a unique set of standards for creative learning. The creativity and innovation pedagogy presented in this work will contribute to the development of emerging engineers capable of designing the technologies and solutions of the future.
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    Intercellular Coupling Abnormalities in the Heart: Quantification from Surface Measurements and Impact on Arrhythmia Vulnerability
    (2016) Ghazanfari, Amin; Nygren, Anders; Vigmond, Edward; Dalton, Colin; Federico, Salvatore; Vinet, Alain
    Cardiac conduction velocity is one of the most important electrophysiological characteristics of the heart. Several cardiac dysfunctions and arrhythmia are caused by slowed conduction velocity. Measurement of cardiac conduction velocity and other physiological characteristics of the heart such as anisotropy ratio are challenged by complex cardiac tissue structure and inaccurate measurement techniques. Diabetes mellitus is an example of a condition that can alter conduction velocity by reducing the electrical coupling between cardiac cells. Diabetes is also known to increase the risk of arrhythmia by increasing the action potential duration of cardiac myocytes. This thesis discusses a measurement method based on fitting ellipses to activation isochrones. Our results show that the intramural fiber rotation caused error in conventional measurement methods used to estimate fiber orientation and anisotropy ratio specially in thinner tissues. These errors are increased by optical mapping measurements specifically in thicker tissues. We developed a mathematical model for the diabetic rabbit ventricular action potential and also used an existing model of the diabetic rat ventricular action potential. We demonstrated the window of vulnerability to reentrant arrhythmia for healthy and diabetic models of both rabbit and rat. Connexin lateralization was modelled in the diabetic models by reducing the gap junction conductivity in the lateral direction. Results demonstrated that window of vulnerability in diabetic rat is smaller than in healthy rat. On the contrary, diabetic rabbit was more vulnerable to reentry than healthy rabbit. The ATP-dependent potassium channel was added to the models and the results demonstrated that diabetic models are more vulnerable to reentry when ischemia occurs and Ikatp channels open consequently.
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    Ischemia-Reperfusion Arrhythmias and Intercellular Coupling in Diabetic and Ischemic-Preconditioned Rat Heart
    (2013-01-30) Randall, Alyssa; Nygren, Anders
    Diabetes and Ischemic Preconditioning (IPC) have been shown in literature to have similar metabolic and microscopic effects on intercellular coupling, conduction reserve, and the response to ischemia-reperfusion in ventricular tissue. Both diabetes and IPC cause reduced intercellular coupling; reduced conduction reserve; and provide cardio-protection to ischemia/reperfusion. To determine the whole heart similarities between IPC and diabetes both electrocardiograph (ECG) and optical mapping data was evaluated. Diabetes displayed different time dependent responses to ischemia/reperfusion from IPC and healthy animals; diabetic animals slow heart rate significantly compared to IPC and control animals during ischemia, while IPC slows conduction velocity. During pacing, IPC and diabetic animals showed similar slowing of conduction velocity though only diabetic animals showed significant slowing in response to reduced cellular excitability. This work suggests IPC and diabetes do not use the same mechanisms to provide cardio-protective effects.
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    Promotion of Peripheral Nerve Regeneration by Uniform Electric Field Application
    (2016) Purdy, Michael; Dalton, Colin; Dalton, Colin; Turner, Raymond W; Nygren, Anders; Syed, Naweed; Fear, Elise
    Peripheral nerve injury is a prevalent condition, afflicting millions of patients around the world and costing the healthcare system billions of dollars. It can lead to sensory loss and debilitating pain, and has a wide range of causes including trauma, infectious diseases, and diabetes. Although peripheral nerves have some inherent ability to regenerate, the recovery process is slow and complex, and regenerative outcomes are limited. However, electrical stimulation has been shown to accelerate recovery. In this work, uniform electric fields are explored in their capacity to encourage neurite outgrowth. A novel microelectrode array is designed to generate uniform fields for application to neurons in vitro, using snail and rat models. In parallel, an implantable nerve cuff was created to apply similar fields in vivo, in injured rat sciatic nerve models. Uniform electric field application was shown to increase overall neuritic outgrowth in snail neurons in vitro.
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    Visualization of atrial arrhythmias
    (2007) Schmidt, Robyn; Leon, Joshua; Nygren, Anders