E-Thesis 215 views
Analysis of Mechanisms Involved in Ventricular Assist Device (VAD) Induced Extracellular Vesicle Generation and their Cellular Effects / REBECCA JAMES
Swansea University Author: REBECCA JAMES
DOI (Published version): 10.23889/SUthesis.60859
Abstract
Heart failure is a major global health issue, carrying a significant risk of morbidity and mortality. The current gold standard treatment for end-stage heart failure is heart transplantation. However, with reduced availability of viable organs, and a non-sustainable treatment strategy, alternate mec...
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Swansea
2022
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Kanamarlapudi, Venkateswarlu |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa60859 |
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| Abstract: |
Heart failure is a major global health issue, carrying a significant risk of morbidity and mortality. The current gold standard treatment for end-stage heart failure is heart transplantation. However, with reduced availability of viable organs, and a non-sustainable treatment strategy, alternate mechanisms are being sought to prolong life. Ventricular assist devices (VADs) offer a potential life-extending treatment, however, do not come without adverse events. Therefore, it is vital to understand and reduce these side effects in order to maximise patient quality of life. More recently, extracellular vesicles (EVs) have increased in popularity amongst various scientific disciplines. EVs are small (<1000 nanometre) membrane-bound packages secreted from all cell types, which are known to have roles in both health and disease. However, there is limited knowledge into the roles of EVs in VAD patients. Therefore, this study investigated the prevalence, origin and roles of EVs concerning VADs. One significant challenge facing EV research is the isolation and detection of EVs, which increases in complexity when assessing EVs in biological fluids that contain numerous components. This study began by assessing the most commonly used isolation and detection techniques and tested their applicability to blood plasma, with mixed results. We demonstrated the need for diluting higher viscosity fluids prior to EV extraction. Secondly, this study displayed the increased prevalence of EVs produced by both leukocytes and platelets exposed to elevated levels of non-physiological shear stress both in vitro and in vivo. We display the effect of VADs as a perpetuating factor in EV production and demonstrated the potential use of EVs as a means of diagnostics in adverse events, to aid in mitigating VAD patient outcomes. Finally, we presented the detrimental effects of elevated pathological EVs in patient prognosis. We assessed cargo alterations within EVs present in both healthy and pathological blood and determined downstream effects. Here, increased levels of leukocyte and platelet EVs are shown to have the potential to induce inflammation and cellular activation. Conversely, we also revealed the therapeutic and disease mitigating potentials of healthy EVs. In conclusion, this study has provided a consensus on the protocol for EV isolation from plasma and a platform for EV research in relation to heart failure and VAD patients. Furthermore, we show VAD shear stress as a significant instigator of EV release. Subsequently, we demonstrate the possibility of healthy EVs in limiting pathological processes. Therefore, this research successfully highlighted the significant impacts of EVs in VAD patients, which can be utilised to improve patient outcomes. |
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| College: |
Faculty of Medicine, Health and Life Sciences |