Browsing by Subject "Cardiac"
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Item Anatomical, Biomechanical, and End-of-Life Considerations for Emergent Cardiac Pacing Technologies(2018-07) Mattson, AlexanderOver 600,000 permanent pacing systems are implanted each calendar year as the primary therapy for symptomatic bradycardia. Innovations in pacing technology have rapidly expanded the indications for this life-saving therapy, while reducing complication rates. This thesis examined three prongs of emergent pacing technologies: leadless pacing, epicardial/extravascular pacing, and physiologic pacing through the bundle of His. First, I quantitatively evaluated the likely target anatomies for next-generation pacing systems. Then, anatomic data was supplemented with biomechanics, to provide the foundation upon which next-generation leadless pacemaker fixation mechanisms may be built. Finally, I investigated some of the challenges of extracting leadless pacing systems. The data in this thesis provided a substrate for the design and implementation of next-generation pacing systems.Item Engineered Cardiac Tissues for Delivery of Cells to the Injured Myocardium(2015-07) Wendel, JacquelineWith the high incidence of heart failure in the developing world and the inherent risks and limited availability of donor hearts, cell-based solutions have become an attractive solution. However, current methods to deliver cells to the heart have resulted in limited long term cell retention and consequently minimal therapeutic efficacy. In this work, we aim to use engineered tissues as a means to deliver cells to the injured myocardium post- infarction with increased cell retention. The results detailed in this dissertation indicate that engineered tissues can be constructed from both primary rodent cardiomyocytes and human pluripotent stem cell derived cardiomyocytes, and that these tissues not only engraft post-infarction with high cell retention , but in some instances also result in improved cardiac function and limitation of left ventricular remodeling postinfarction.Item Predictors for participation in a cardiac rehabilitation program feasibility study.(2009-12) Krisko-Hagel, Kathryn AnnOBJECTIVE: Feasibility study, to explore whether stage of readiness, level of selfefficacy, or perceived benefits/barriers to begin a cardiac rehabilitation (CR) program post cardiac event are associated with the length of time individuals will participate in a Phase II CR program. BACKGROUND: “Stages of Behavior Change” from the Transtheoretical Model (TTM) of Health Behavior. Self-efficacy is one of the constructs of the TTM. Perceived benefits and barriers apply to an individual’s belief system regarding a needed course of action. AIMS: To generate an effect size for: (1) possible association between stage of readiness; (2) level of self-efficacy; and (3) perceived benefits or barriers related to CR post cardiac event and their possible association with meeting CR goals and/or length of time in the program. DESIGN AND METHOD: Prospective correlational design using a convenience sample of men and women having experienced a cardiac event who have received a physician’s order to attend a Phase II CR program. PROCEDURE: The sample was taken from one CR center located in one tertiary care center. Data were collected over a two-month period of time. FINDINGS: A significant association was found between the level of self-efficacy to begin CR and the percentage of CR goals met and a moderate association noted between the level of self-efficacy to begin CR and length of time in the program. CONCLUSIONS: The higher the self-efficacy, the more likely individuals were to remain in CR. Other variables discovered to be of interest were perceived health before the cardiac event, perceived health "now," and perceived health in six months time. IMPLICATIONS: Accurate nursing assessments could help change adverse outcomes by identifying those at risk of not completing CR. Interventions by the nurse through encouragement (to help raise level of self-efficacy of the individual and through family teaching) could help improve completion outcomes.Item The Role of Cardiac Troponin I as an Allosteric Regulator of Sarcomere Activation(2017-12) Vetter, AnthonyThe cardiac sarcomere is the functional unit of force production in the heart. The sarcomere is a highly ordered near-liquid crystalline arrays of thin and thick filament proteins held in stoichiometric balance that work in a concerted fashion to orchestrate the heart’s pump function. Regulation of cardiac output is mediated by a combination of myocyte cell-intrinsic and cell-extrinsic factors that fine-tune the contractile machinery. Central to the regulation of the sarcomere is the heterotrimeric cardiac troponin complex (cTn) whose subunits include: cardiac troponin T (cTnT), an adaptor protein that tethers cTn into the ultrastructure of the thin filament via tropomyosin; cardiac troponin C (cTnC), a calmodulin-like EF-hand protein that confers calcium sensitivity to the thin filament; and cardiac troponin I (cTnI), a molecular switch that toggles between the actin filament and N-terminal lobe of cTnC. When associated with actin, cTnI prevents the azimuthal rotation of tropomyosin along the filament thereby concealing strong myosin binding sites along the thin filament. Therefore, cTn may be thought of as a binary switch regulated by calcium, toggling cTnI between the actin-associated inhibitory state and the cTnC-associated active state. The penultimate outcome of this dynamic structural process is changing the steric accessibility of myosin binding sites to cycling force producing myosin cross-bridges. Alterations in the sarcomeric structure-function relationship by both cell-intrinsic and cell-extrinsic factors underlie the pathology of numerous acquired and inherited cardiomyopathies. As such, gaining a greater understanding of the activation, inactivation, and molecular interactions within the sarcomere underpins and enables our ability to redress heart failure. For decades, tools have long been available to quantitatively detect and monitor the sarcolemmal depolarization and calcium transient that initiate contraction. Furthermore, the final output of the contractile machinery can be monitored by a variety of tools that measure the force production of the sarcomere. However, to this date, there has been a “black box” around the intervening processes which govern the sarcomere activation under physiological conditions. A preponderance of evidence derived from studies of isolated proteins, electron microscopy, and permeabilized steady-state muscle fibers has supported the theory that strong myosin binding is requisite to activate the sarcomere. However informative these studies are, they are limited by their non-physiological experimental conditions. Here, ex vivo cellular physiology enabled by a novel live-cell biosensor and in silico molecular dynamics simulations were used in tandem to investigate the activation of the sarcomere and specifically how the cTnC:cTnI interface is a critical juncture for determining contractility under physiological conditions. Evidence suggests that in juxtaposition to the long-standing three-state model wherein myosin binding to actin is necessary to shift the equilibrium of cTn complexes from the closed to the open state, calcium and cTnI switch peptide binding are sufficient to activate the sarcomere and permit force production by cycling cross-bridges under the live cell conditions described herein. Furthermore, when cTnI binds to the N-terminal lobe of cTnC, the interaction between helix 4 of cTnI and the A helix of cTnC is a primary determinant of contractility independent of changes in the calcium-transient. Collectively, this work enhances our knowledge of how the cardiac sarcomere is regulated and establishes it as a potent therapeutic target to improve heart pump function in ailing myocardium.Item The Role of Oxidative Stress in Remodeling the Cardiac Microtubule Cytoskeleton(2021-05) Goldblum, RebeccaMicrotubules are cylindrical cytoskeletal polymers composed of α/β-tubulin heterodimers that make up an ordered tubulin lattice. In cells, microtubules form a network that is a key component of the cellular cytoskeleton. Under pathological conditions of oxidative stress, we and others have found that cardiomyocytes, the contractile cells in the heart, display a denser microtubule cytoskeleton, which may lead to the progressive structural and functional cellular changes associated with myocardial ischemia and systolic dysfunction. This reorganization of the microtubule network occurs despite only small increases in tubulin expression, suggesting that alterations to microtubule length regulation and stability are involved. Using biophysical reconstitution experiments and live-cell imaging, we found that oxidative stress may synergistically increase the density of microtubules inside of cells by simultaneously increasing the length of dynamic, short-lived microtubules, while fostering the longevity of stable, long-lived microtubules. We found that microtubules subjected to oxidative stress undergo cysteine oxidation, and our electron and fluorescence microscopy experiments revealed that the locations of oxidized tubulin subunits within the microtubule had structural damage within the cylindrical tubulin lattice, consisting of holes and lattice openings. For dynamic microtubules, incorporation of stabilizing GTP-tubulin into these damaged lattice regions led to an increased frequency of rescue events (the transition from shortening to growth), and thus longer microtubules. For long-lived microtubules, these same structural defects facilitate entry of the enzyme αTAT1 into the microtubule lumen, where it catalyzes the acetylation of α-tubulin. This intraluminal acetylation has been shown to increase the lifetime of stable microtubules by conferring mechanical stability to the microtubule lattice. In this way, oxidative stress triggers a dramatic, pathogenic shift from a sparse microtubule network into a dense, longitudinally aligned microtubule network inside of cardiac myocytes, likely contributing to increased cellular stiffness and contractile dysfunction. Our results provide insight into myocardial changes in ischemic heart disease by describing a mechanism for the dramatic remodeling of the microtubule cytoskeletal network within cardiac myocytes subjected to oxidative stress.Item Tuning the Equilibrium: A Biophysical Approach to Controlling Cardiac Contractility through SERCA and Phospholamban(2017-05) Soller, KaileyHeart disease is the leading cause of death throughout the world and one of the major hallmarks is dysfunctional muscle contractility. Contractility is a highly regulated and complex process which involves multiple proteins. This network can be easily disrupted by mutation or changes in protein expression level and thus, proteins involved in this process are key drug targets. Muscle contractility is controlled by the calcium concentration in the cytosol. In cardiomyocytes, the sarco(endo)plasmic reticulum Ca2+ -ATPase, SERCA, and its regulatory protein, phospholamban (PLN) are responsible for ~70% of Ca2+ reuptake into the SR. While unphosphorylated, PLN inhibits SERCA by lowering its apparent Ca2+ affinity. Upon phosphorylation by PKA at Ser16, PLN inhibition is relieved. Mutations or disruptions in this complex have found in many forms of heart disease; thus, understanding the molecular interactions between SERCA and PLN, along with possible regulatory molecules, is essential. Understanding the molecular mechanisms that occur on a beat-to-beat basis will be essential for developing therapeutics to treat cardiomyopathies. In this dissertation work, I studied the structural, biochemical and biophysical properties of SERCA and PLN. We found that single-stranded DNA (ssDNA), RNA, and DNA analogs bind the cytoplasmic domain of PLN with low nanomolar dissociation constants, relieving inhibition of SERCA. The relief of inhibition is length-dependent, while affinity is constant for oligonucleotides longer than 10 bases. Solution and solid-state NMR experiments have provided residue specific information that ssDNA targets the cytoplasmic domain of PLN and does not affect SERCA in the absence of PLN. In-cell FRET and NMR experiments determined that addition of ssDNA does not dissociate PLN from SERCA. Additionally, I started moving this work into a sustainable, in vivo system using cardiomyocytes derived from induced pluripotent stem cells (iPSCs) to investigate the functional effects of these molecules with PLN in cell. The establishment of this cell line in our laboratory will allow for future characterization of not only XNAs with PLN, but also experiments with any cell type obtainable through differentiation of iPSCs. Finally, early work with the R14del hereditary mutant of PLN helped to determine the structural changes this mutant imposes on PLN as well as when in complex with SERCA. We found that the R14del mutant is loss-of-function and also if phosphorylated, will not relieve inhibition of SERCA. We believe that the knowledge gained here on the SERCA-PLN complex contributes to the overall understanding of how calcium handling can be modulated to change protein function and demonstrates a novel avenue of oligonucleotide action in the body. miRNAs may have evolved to also directly interact with non-transcription related proteins to modulate their function. These results and our future experiments will provide a promising avenue for development of novel therapeutic regulators of the SERCA-PLN complex to help treat heart disease, as well as provide some of the needed mechanistic insight on how hereditary mutants like R14del cause aberrant regulation in the heart.Item Which NSAID Pain Relievers Should I Use If I Have Heart Disease Risk?(2009-08-20) Bohman, J. KyleCommon pain relievers including NSAIDs, Aspirin and COX-2 inhibitors have been shown to have varying degrees of cardiac disease risk and gastritis risk. The choice between pain relievers depends on an individual’s risk factors and tolerance of side effects.