Browsing by Subject "Heart"

Now showing 1 - 4 of 4
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    Effect of constant-DI pacing on single cell cardiac dynamics
    (2020-09) Parthiban, Preethy
    Cardiac alternans, beat-to-beat alternations in action potential duration (APD), is a precursor to fatal arrhythmias such as ventricular fibrillation (VF). Previous research has shown that voltage driven alternans can be suppressed by application of constant diastolic interval (DI) pacing protocol. However, the effect of constant-DI pacing on cardiac cell dynamics and its interaction with the intracellular calcium cycle remains to be determined. Therefore, we aimed to examine the effects of constant-DI pacing on the dynamical behavior of isolated cardiac myocytes along with the influence of voltage-calcium (V-Ca) coupling on these changes. Cardiac cell dynamics were analyzed in a non-linear neighborhood close to the bifurcation point using a hybrid pacing protocol, a combination of periodic and constant-DI pacing. We demonstrated that in a small region beneath the bifurcation point constant-DI pacing caused the cardiac cell to remain alternans-free after switching to the constant-BCL pacing, thus introducing a region of bistability (RB). Strong V-Ca coupling increased the size of the RB. Overall, our findings demonstrate that experimental constant-DI pacing on cardiac cells with strong V-Ca strength may induce permanent changes to cardiac cell dynamics increasing the utility of constant-DI pacing.
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    Eigenvalue based alternans prediction and the effects of heart rate variability on alternans formation
    (2013-06) Kakade, Virendra Vilas
    Ventricular fibrillation, a leading cause of death in the US, is an instability observed at the whole heart level which may result from the alternation of action potential viz. alternans at the cellular level. Previous approaches to predict alternans formation are based on the slope of the restitution curve which is the relation between the action potential duration (APD) and the duration of the preceding diastolic interval (DI). These approaches propose that alternans exists when the slope of this curve is greater than one and ceases to exist otherwise. However restitution based approaches have not been successful in all cases. One of the shortcomings of restitution approach is the non-uniqueness of the restitution curve which results from the variety of pacing protocols used to construct it. This has lead to observations in which alternans existed when the slope was less than one and vice a versa. Moreover restitution approaches use just one measurement from each action potential(AP). Another shortcoming of these approaches is periodic pacing, which is employed to attain the responses (APD and DI) at different basic cycle lengths (BCL) to construct the restitution curve. Upon analysis of electrocardiograms, it is evident that natural pacing is not periodic and exhibits rate variability which can be seen from measurement of RR intervals (which are analogous to BCL) over time. It would be beneficial to develop a method which is not very related to the restitution approach to predict alternans formation and which would not necessitate the generation of a curve and thus reduce errors introduced due to slope calculation. Such a method could also use multiple measurements from each AP to characterize it. Also, it would be beneficial to study the effects of introducing variability in pacing, on alternans formation. Analysis of such data would give us some valuable insight into the complex phenomenon of alternans. With these two shortcomings in sight two studies were conducted with specific aims as follows:Aim1: Apply a dominant eigenvalue method to predict alternans formation in the rabbit heart. A dominant eigenvalue based alternans prediction was recently developed and tested on data obtained from single cell numerical simulation data. I applied this technique at whole heart level to test whether alternans formation could be predicted using a eigenvalue calculated at each BCL from AP response data. I found that the eigenvalue showed decreasing trend towards the value of -1 as BCL was decreased and approached alternans onset. Aim2: Study the effect of introducing rate variability in pacing on a ionic model of a single cell. Ionic model of a single cell was paced using two protocols which introduced variability in the pacing rate by either varying the BCL or DI to test the effects on alternans formation. It was found that introducing variability using first method (varying BCL) lead to alternans formation over wider range of BCL than without variability. The second method (varying DI) however did not give rise to alternans in the model with or without variability.
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    Enterococcus faecalis aggregation substance (Asc10) as liaison between bacterium and heart valve in endocarditis.
    (2009-08) Chuang-Smith, Olivia Newton
    Aggregation Substance proteins encoded by sex pheromone plasmids increase virulence of Enterococcus faecalis in experimental pathogenesis models, including infectious endocarditis. These large surface proteins may contain multiple functional domains involved in various interactions with other bacterial cells and with the mammalian host. Aggregation Substance Asc10, encoded by the plasmid pCF10, is induced during growth in the mammalian bloodstream, and pCF10 carriage gives E. faecalis a significant selective advantage in this environment. We employed a rabbit model to investigate the role of various functional domains of Asc10 in endocarditis. The data suggested that the bacterial load of the vegetation was the best indicator of virulence. Previously identified aggregation domains contributed to the virulence associated with the wild-type protein, and a strain expressing an Asc10 derivative where glycine residues in two RGD motifs were changed to alanines showed the greatest reduction in virulence. Remarkably this strain, and the strain carrying the pCF10 derivative with the in-frame deletion of prgB were both significantly less virulent than an isogenic plasmid-free strain. In addition, mutants carrying Tn917 insertions in the prgB gene demonstrated that secreted N-terminal Asc10 fragments possess activity promoting endocarditis virulence. The data demonstrate that multiple functional domains are important in Asc10-mediated interactions with the host during the course of experimental endocarditis, and that in the absence of a functional prgB gene, pCF10 carriage is actually disadvantageous in vivo. Since Asc10 is important as a virulence factor in E. faecalis endocarditis pathogenesis, developing immunization approaches against this surface protein will be useful in combating endocarditis disease. Use of Fab fragment antibodies against Asc10 was found to decrease vegetation size and bacterial load in the rabbit endocarditis model. In addition, microarray and histological studies revealed two routes of infection in vegetation formation; one in the absence of Asc10, characterized by a robust inflammatory response, and the second in which the presence of Asc10 dampens this response, possibly impeding the influx of immune cells into the vegetation. We also employed an ex vivo porcine heart valve adherence model to study the initial interactions between Asc10+ E. faecalis and valve tissue, and to examine formation of biofilms. We found that the aggregation domains contribute most to Asc10-mediated E. faecalis valve adherence, whereas the RGD motifs have importance in later stages of valve colonization. Again, an N-terminal Asc10 fragment expressed from a prgB Tn917 insertion mutant mediated adherence of E. faecalis cells, emphasizing the importance of the aggregation domains in valve attachment. Most of the Asc10 mutants examined showed some defects in valve adherence at 4 h, corroborating results from our rabbit endocarditis model, and implying that Asc10 contributes mainly to persistence of E. faecalis during endocarditis infection. Extracellular matrix (ECM) protein studies to determine the eukaryotic Asc10 ligand in valve tissue found that fulllength Asc10 protein did not mediate E. faecalis binding to vitronectin, fibronectin, fibrinogen, von Willebrand factor, heparan sulfate, or chondroitin sulfate. In scanning electron microscopy analysis of the infected valve tissue, we found evidence of biofilm formation, including growing aggregates of bacteria, and the increasing presence of exopolymeric matrix over time. Additionally, E. faecalis cells preferentially bound to damaged tissue, though it was difficult to determine whether the bacteria caused the damage, or if it was due to deterioration of the tissue over time. This porcine heart valve tissue colonization model will serve as a useful tool in future studies of biofilm formation.
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    Novel therapies for hypertension and associated cardiovascular risk
    (2018-08) Annoni, Elizabeth
    This thesis is comprised of two parts. The first part investigates a novel therapy, vagus nerve stimulation, for hypertension and hypertension-induced heart disease. Hypertension impacts over 1 billion people worldwide, and clinical management is challenging. Left uncontrolled, high blood pressure can significantly increase the risk of cardiovascular events. The majority of hypertensive patients are treated with anti-hypertensive drugs to control blood pressure, but many limitations exist including resistant hypertension, inability to tolerate therapy, and non-compliance with the medication regime. For these patients, an alternative approach is needed to control blood pressure. Recently, the imbalance in the autonomic nervous system, evident in hypertension, has been the target of novel device-based therapies such as vagus nerve stimulation. The main goal of this research is to evaluate the efficacy of vagus nerve stimulation to treat hypertension and hypertension-induced heart disease. This thesis investigates the impact of vagus nerve stimulation on disease progression, survival, and cardiovascular remodeling in Dahl salt-sensitive hypertensive rats. Overall, the results of this work provide evidence for the beneficial therapeutic effects of vagus nerve stimulation in hypertension and motivate future studies to optimize therapy parameters and further understand therapeutic mechanisms. The second part of this thesis focuses on atrial fibrillation and the evaluation of new mapping techniques for improving rotor localization for ablation procedures. Currently, success rates for ablation procedures for non-paroxysmal atrial fibrillation are low and require repeat procedures or a lifetime of pharmacological agents to reduce the risk of stroke. Improved signal processing techniques for mapping electrical activity in the atrium can help further our understanding of the generation and maintenance of atrial fibrillation and ultimately improve ablation procedure success rates and terminate the arrhythmia. The main goal of this work was to validate new signal processing techniques – multiscale frequency, kurtosis, Shannon entropy, and multiscale entropy – to identify regions of abnormal electrical activity. The results of this work demonstrate improved accuracy of these novel techniques in mapping rotors in cardiac arrhythmias and motivates further studies evaluating more complex arrhythmias and human intracardiac electrograms.