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Author: Yun Qiao (Biomedical engineer)
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 104
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Book Description
In the last two decades, our understanding of cardiac arrhythmias has been accelerated immensely by the development of genetically engineered animals. Transgenic and knockout mice have been the "gold standard" platforms for delineating disease mechanisms. Much of our understanding of the pathogenesis of atrial and ventricular arrhythmias is gained from mouse models that alter the expression of specific ion channels or other proteins. However, cardiac arrhythmias such as atrial fibrillation are heterogeneous diseases with numerous distinct conditions that could not be explained exclusively by the disruption of ionic currents. Increasing evidence suggests disruption of signaling pathways in the pathogenesis of cardiac arrhythmias. Although crucial for studying disease mechanisms, animal models often fail to predict human response to treatments due to inter-species genetic and physiological differences. Cardiac slices obtained from human hearts have been demonstrated as an accurate model that more faithfully recapitulates human cardiac physiology. However, the use of the human cardiac slices for evaluating the transcriptional regulation of arrhythmia is hampered by tissue remodeling and dedifferentiation in long-term culture of the slices. The first part of this dissertation aims to elucidate one of the potential mechanisms of sick sinus syndrome and atrial fibrillation induced by transient reactivation of Notch, a critical transcription factor during cardiac development and has been shown to be reactivated in the adult heart following cardiac injury. When Notch is transiently reactivated in the adult mice to mimic the injury response, the animals exhibits slowed heart rate, increased heart rate variability, frequent sinus pauses, and slowed atrial conduction. The electrical remodeling of the atrial myocardium results in increased susceptibility to atrial fibrillation. The transient reactivation of Notch also significantly altered the atrial gene expression profile, with many of the disrupted genes associated with cardiac arrhythmias by genome-wide association study. The second part of this dissertation aims to address the lack the translation from animal research to human therapies by extending the human cardiac slice viability in culture. With the optimized culture parameters, human cardiac slices obtained from the left ventricular free wall remained electrically viable for up to 21 days in vitro and routinely maintained normal electrophysiology for up to 4 days. To genetically alter the human cardiac slices, a localized gene delivery technique was evaluated and optimized. The third part of the dissertation aims to further improve long-term culture of human cardiac slices and to increase the availability of human tissue for research by developing a self-contained heart-on-a-chip system for automated culture of human cardiac slices. The system maintains optimal culture conditions and provides electrical stimulation and mechanical anchoring to minimize tissue dedifferentiation. The work allows for accelerated optimization of long-term culturing of human cardiac slice, which will enable study of arrhythmia mechanisms on human cardiac tissue via targeted control of transcription factors.
Author: Yun Qiao (Biomedical engineer)
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 104
Get Book Here
Book Description
In the last two decades, our understanding of cardiac arrhythmias has been accelerated immensely by the development of genetically engineered animals. Transgenic and knockout mice have been the "gold standard" platforms for delineating disease mechanisms. Much of our understanding of the pathogenesis of atrial and ventricular arrhythmias is gained from mouse models that alter the expression of specific ion channels or other proteins. However, cardiac arrhythmias such as atrial fibrillation are heterogeneous diseases with numerous distinct conditions that could not be explained exclusively by the disruption of ionic currents. Increasing evidence suggests disruption of signaling pathways in the pathogenesis of cardiac arrhythmias. Although crucial for studying disease mechanisms, animal models often fail to predict human response to treatments due to inter-species genetic and physiological differences. Cardiac slices obtained from human hearts have been demonstrated as an accurate model that more faithfully recapitulates human cardiac physiology. However, the use of the human cardiac slices for evaluating the transcriptional regulation of arrhythmia is hampered by tissue remodeling and dedifferentiation in long-term culture of the slices. The first part of this dissertation aims to elucidate one of the potential mechanisms of sick sinus syndrome and atrial fibrillation induced by transient reactivation of Notch, a critical transcription factor during cardiac development and has been shown to be reactivated in the adult heart following cardiac injury. When Notch is transiently reactivated in the adult mice to mimic the injury response, the animals exhibits slowed heart rate, increased heart rate variability, frequent sinus pauses, and slowed atrial conduction. The electrical remodeling of the atrial myocardium results in increased susceptibility to atrial fibrillation. The transient reactivation of Notch also significantly altered the atrial gene expression profile, with many of the disrupted genes associated with cardiac arrhythmias by genome-wide association study. The second part of this dissertation aims to address the lack the translation from animal research to human therapies by extending the human cardiac slice viability in culture. With the optimized culture parameters, human cardiac slices obtained from the left ventricular free wall remained electrically viable for up to 21 days in vitro and routinely maintained normal electrophysiology for up to 4 days. To genetically alter the human cardiac slices, a localized gene delivery technique was evaluated and optimized. The third part of the dissertation aims to further improve long-term culture of human cardiac slices and to increase the availability of human tissue for research by developing a self-contained heart-on-a-chip system for automated culture of human cardiac slices. The system maintains optimal culture conditions and provides electrical stimulation and mechanical anchoring to minimize tissue dedifferentiation. The work allows for accelerated optimization of long-term culturing of human cardiac slice, which will enable study of arrhythmia mechanisms on human cardiac tissue via targeted control of transcription factors.
Author: Toshio Nakanishi
Publisher: Springer Nature
ISBN: 9811511853
Category : Medical
Languages : en
Pages : 374
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Book Description
This open access book focuses on the molecular mechanism of congenital heart disease and pulmonary hypertension, offering new insights into the development of pulmonary circulation and the ductus arteriosus. It describes in detail the molecular mechanisms involved in the development and morphogenesis of the heart, lungs and ductus arteriosus, covering a range of topics such as gene functions, growth factors, transcription factors and cellular interactions, as well as stem cell engineering technologies. The book also presents recent advances in our understanding of the molecular mechanism of lung development, pulmonary hypertension and molecular regulation of the ductus arteriosus. As such, it is an ideal resource for physicians, scientists and investigators interested in the latest findings on the origins of congenital heart disease and potential future therapies involving pulmonary circulation/hypertension and the ductus arteriosus.
Author: Malou van den Boogaard
Publisher:
ISBN: 9789082488722
Category :
Languages : en
Pages : 0
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Book Description
"The coordinated contraction of the heart relies on proper functioning of ion channels that generate the cardiac electrical impulse. Inappropriate regulation of these ion channels can result in a wide variety of cardiac arrhythmias. Mutations in the genetic code of genes encoding cardiac ion channels are an important cause of cardiac arrhythmias. Increasing evidence shows that genetic variation in noncoding regulatory regions can disturb important biological processes, thereby adding to the complexity of heritable diseases. This thesis explores the role of noncoding regulatory elements and the effects of genetic variants therein on cardiac ion channel gene expression and function. Using current state-of-the-art techniques we identified several regulatory elements in the vicinity of ion channel genes. We show that loss of these regulatory elements results in reduced expression of ion channel genes, which consequently affects cardiac conduction. Furthermore, we provide evidence that genetic variants herein affect ion channel gene expression in humans. These insights will help to stratify the risk of arrhythmia and will provide clues towards developing novel therapeutic strategies that can bring personalized medicine closer to clinical application."--Samenvatting auteur.
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Author: Rich Gang Li
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Cardiac arrhythmias affects millions of Americans and can lead to sudden cardiac death, accounting for more than 300,000 deaths annually. Despite the vast knowledge available for cardiac disease and associated arrhythmias, very few effective therapies exist. Current interventions include cardioverter defibrillators and antiarrhythmic drugs targeting ion channels or the [beta]-adrenergic pathway. In most acquired and inherited arrhythmias, molecular signaling pathways are perturbed. However, little is known about the underlying mechanism of how these signaling pathways regulate cardiac electrophysiology. Therefore, a better understanding of major signaling pathways governing cardiac development or dysregulated in cardiac disease could lead to novel therapeutics for the treatment of arrhythmias. In my thesis dissertation, I show that the Wnt signaling pathway directly regulates genes relevant for cardiac electrophysiology in both the embryonic and adult murine heart. Additionally, I found that pharmacologic inhibition of the glycogen synthase kinase 3 pathway in the adult human heart results in electrophysiological changes that could contribute to an arrhythmogenic substrate.In the first part of my thesis, I show that developmental perturbation of Wnt signaling leads to chamber-specific transcriptional regulation of genes important in cardiac conduction that persists into adulthood. Transcriptional profiling of right versus left ventricles in mice deficient in Wnt transcriptional activity reveals global chamber differences, including genes regulating cardiac electrophysiology such as Gja1 and Scn5a. In addition, the transcriptional repressor Hey2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle only. These transcriptional changes lead to perturbed right ventricular cardiac conduction and cellular excitability. Ex vivo and in vivo stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. These data show that embryonic perturbation of Wnt signaling in cardiomyocytes leads to right ventricular arrhythmia susceptibility in the adult heart through chamber-specific regulation of genes regulating cellular electrophysiology.In the second part of my thesis, I use a human cardiac slice culture platform to show that inhibition of glycogen synthase kinase 3 (GSK-3) pathway alters the cardiac electrical substrate. Glycogen synthase kinase 3 (GSK-3) is a multifunctional regulatory kinase that has emerged as a potential therapeutic target for several diseases, including cancer, diabetes, and bipolar disorder. In the heart, dysregulation of GSK-3 has been implicated in pathological conditions such as cardiac hypertrophy, ischemic injury, and heart failure, which are often accompanied by arrhythmias. Despite growing evidence that dysregulation of GSK-3 is associated with arrhythmias, the precise role for GSK-3 regulation of human cardiac electrophysiology remains poorly defined. Human cardiac slices cultured with the GSK-3 inhibitor SB216763 showed reduced conduction velocity at 3 and 24 hours in culture compared to vehicle controls. Action potential measurements revealed decreased excitability in GSK-3 treated slices, as measured by decreased dVm/dtmax. Computational simulations demonstrated that decreased sodium channel conductance and tissue conductivity are plausible causes for observed reduction in conduction velocity and dVm/dtmax. [beta]-catenin, a target of GSK-3 and the transcriptional effector of Wnt signaling, increased within cardiomyocyte nuclei as expected. However, transcription of Wnt/[beta]-catenin target genes and SCN5A were unchanged, while NaV1.5 protein, the major cardiac sodium channel subunit, decreased after 3 hours in culture with SB216763. This suggests that acute GSK-3 inhibition-mediated regulation of cardiac electrophysiology can occur in part through post-transcriptional mechanisms, and that therapeutic strategies targeting the GSK-3 pathway may be associated with an increase in adverse cardiovascular effects.I demonstrate here that two inter-related signaling pathways, Wnt and GSK-3, regulate cardiac electrophysiology through modulation of ion channels regulating cardiac conduction via transcriptional and post-transcriptional mechanisms. In addition to the contribution to basic research through advancing our overall understanding of molecular signaling pathways in cardiac conduction and arrhythmias, these results may provide insight for translational pre-clinical research to aid in the development of novel antiarrhythmic drugs.
Author: Catherine Elise Lipovsky
Publisher:
ISBN:
Category : Electronic dissertations
Languages : en
Pages : 344
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Book Description
Abnormalities in electrical impulse generation and/or propagation that affect the heart's normal rhythm are extremely common. Clinically, cardiac arrhythmias are prevalent worldwide, yet the molecular mechanisms underlying their pathology remain largely unknown. Current treatments for arrhythmias primarily target symptoms rather than the underlying cause and these treatments have limited efficacy. The most common risk factor for developing an arrhythmia is a previous cardiac injury; however, the mechanisms underlying this are not well described. My thesis work has demonstrated that the Notch signaling pathway, which is crucial for cardiac patterning and development and is normally quiescent in adult cardiomyocytes (CMs), is reactivated in the adult heart following cardiac injuries that predispose to arrhythmias, such as myocardial infarction. Notch activation within the adult heart leads to changes in cardiac electrophysiology and gene expression in the right atrial (RA) chamber. We have shown that these chamber-specific changes persist even one year after a short pulse of Notch signaling activation, suggesting that even a small level of Notch signaling activation following cardiac injury is sufficient to cause long-term functional changes in cardiac electrophysiology. These mice develop conduction abnormalities akin to sick sinus syndrome (SSS) in humans, a disorder that predisposes an individual to atrial fibrillation (AF). Understanding molecular determinants in the pathogenesis of AF is crucial because it is the most common cardiac arrhythmia that affects up to 2% of the general population. AF represents a significant source of morbidity and mortality as it increases the risk of stroke and heart failure (HF). Current research has proposed that AF can be caused by multiple factors including genetics (such as mutations in coding or non-coding parts of the genome) and/or environmental factors (such as hypertension and diabetes). Past research has focused on genome-wide association studies to elucidate factors involved in AF; however, this limits our understanding of AF pathogenesis to genetic variation. In AF, triggers are believed to originate in the pulmonary veins (PVs) near the posterior left atrium (LA), and the LA itself is remodeled to create a substrate conducive for arrhythmia maintenance. My work found that Notch signaling is also re-activated in the LA following cardiac injury, suggesting Notch signaling may potentially be acting as an environmental factor that could predispose to AF. Based on my findings that Notch can cause changes to RA electrophysiology, I hypothesized Notch could also be causing electrophysiological changes in the LA. Traditionally, cardiac research has lumped ventricular chambers and atrial chambers together as similar units, but it is becoming increasingly clear that each cardiac chamber represents a distinct transcriptional unit that has a differential response to injury signals. Indeed, we characterized how Notch signaling electrically remodels the LA to predispose to AF and found that Notch signaling differentially affects ion channel gene expression in the RA versus the LA, even within the heart of the same mouse. Furthermore, cardiac electrophysiology of the RA shows an opposite phenotype than in the LA. Whereas Notch signaling affects Na+ channel gene expression and function by altering the Phase 0 of the action potential in the RA and therefore decreases CM excitability, K+ channel genes appear to be the main ion channels affected in the LA. Alterations to K+ channel genes leads to action potential duration (APD) prolongation, similar to the action potential phenotype seen in previously published work from the Moskowitz lab on a Tbx5 loss-of-function (LOF) mouse model of AF. Furthermore, RNA-sequencing performed by our lab on CM nuclei isolated from the LA of human AF patients revealed that Notch signaling is significantly upregulated compared to the LA of non-AF patients. Collectively, our findings demonstrate for the first time that activation of Notch signaling is associated with AF in both mouse models and human tissue, suggesting that Notch signaling is an environmental risk factor that can transiently turn on following cardiac injury. As a result, Notch activation leads to differential electrophysiological remodeling in the RA versus the LA and predisposes the heart to arrhythmias. Differential atrial remodeling could help explain why cardiac injury is the largest risk factor for developing an arrhythmia and could further explain why current treatments for arrhythmias are often ineffective and paradoxically pro-arrhythmic. Therefore, since each cardiac chamber has a differential response to injury, they should not be treated equally. In summary, my thesis work can be a blueprint for targeting arrhythmia treatments on individual chambers rather than treating the heart as a single unit. Furthermore, Notch signaling may be a potential target for inhibition following cardiac injury to prevent cardiac electrical remodeling and the development of potentially life-threatening arrhythmias.
Author: Rodney Michael Dale
Publisher:
ISBN: 9780549010425
Category : Genetic regulation
Languages : en
Pages : 252
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Book Description
Friend of GATA (FOG)-2 is a transcriptional co-repressor critical for cardiac development. Mice deficient in FOG-2 die at embryonic day (E)13.5 of congestive heart failure due to severe cardiac malformations. FOG-2 expression is first observed in the developing heart and the pro-epicardium at E8.5. By E16.5, FOG-2 is predominantly expressed in the brain, heart, and gonads. Despite FOG-2's critical role in cardiac development, little is known about the early cardiac-restricted regulation of the FOG-2 gene.
Author: Eric Matthew Small
Publisher:
ISBN:
Category : Genetic transcription
Languages : en
Pages :
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Book Description
Author: José Marín-García
Publisher: Academic Press
ISBN: 0124046428
Category : Medical
Languages : en
Pages : 935
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Book Description
In this second edition of Post-Genomic Cardiology, developing and new technologies such as translational genomics, next generation sequencing (NGS), bioinformatics, and systems biology in molecular cardiology are assessed in light of their therapeutic potential. As new methods of mutation screening emerge, both for the genome and for the “epigenome, comprehensive understanding of the many mutations that underlie cardiovascular diseases and adverse drug reactions is within our reach. This book, written by respected cardiologist José Marín-García, features discussion on the Hap-Map: the largest international effort to date aiming to define the differences between our individual genomes. This unique reference further reviews and investigates genome sequences from our evolutionary relatives that could help us decipher the signals of genes, and offers a comprehensive and critical evaluation of regulatory elements from the complicated network of the background DNA. Offers updated discussion of cutting-edge molecular techniques including new genomic sequencing / NGS / Hap-Map / bioinformatics / systems biology approaches Analyzes mitochondria dynamics and their role in cardiac dysfunction, up-to-date analysis of cardio-protection, and cardio-metabolic syndrome Presents recent translational studies, gene therapy, transplantation of stem cells, and pharmacological treatments in CVDs
Author: Benoit G. Bruneau
Publisher:
ISBN: 9781621823582
Category : Medical
Languages : en
Pages : 0
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Book Description
Development of the heart is a complex process and can lead to serious congenital disease if the process goes awry. This book provides a detailed description of the cell lineages involved in heart development and how their migration and morphogenesis are controlled. It also examines the genetic and environmental bases for congenital heart disease and how model systems are revealing more about the processes involved. Topics covered in this essential volume include: - Anatomy of a Developing Heart - Genetic and Epigenetic Control of Heart Development - Development of the Cardiac Conduction System - Genetic Basis of Human Congenital Heart Disease - In Vivo and In Vitro Genetic Models of Congenital Heart Disease
Author: Michael Artman
Publisher: Wiley-Blackwell
ISBN: 1405131284
Category : Medical
Languages : en
Pages : 320
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Book Description
Congenital cardiovascular malformations are the single most common form of birth defect. Therefore a better understanding of the mechanisms involved in both normal cardiac development and the formation of cardiovascular structural defects is of tremendous importance. This book brings together the leading scientists from around the world who are actively engaged in studies of the etiology, morphogenesis and physiology of congenital cardiovascular diseases. A broad variety of approaches, techniques, experimental models and studies of human genetics combine to make this a truly outstanding and unique treatise on this pressing topic. Cardiovascular Development and Congenital Malformations is divided into distinct categories, each focusing on a particular aspect of cardiovascular development. Sections are accompanied by editorial overviews which integrate new findings and place the information into a broader context.
