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Splenic Control of Cardiovascular Homeostasis: the role of the spleen in the pathogenesis of cardiovascular disease

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Title: Splenic Control of Cardiovascular Homeostasis: the role of the spleen in the pathogenesis of cardiovascular disease
Author: Huber, Jason Sean
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Simpson, Jeremy
Abstract: The spleen is largely classified as redundant, non-vital or even vestigial due to excellent near-term patient outcomes following splenectomy. Epidemiological studies identify that splenectomy, in the long-term, is associated with increased risk for the development of cardiovascular disease and diabetes. This suggests that the spleen plays a key role in maintaining cardiovascular homeostasis that has yet to be identified. Subsequent investigations, where splenectomy is performed in models of pre-existing diseases, indicate the spleen is an important modulator of inflammation (i.e., splenectomy caused exacerbation or attenuation of the model). The underlying assumption is the spleen does not contribute to cardiovascular homeostasis. Furthermore, there is a lack of sex comparisons despite sex differences in the prevalence, clinical manifestation and pathophysiology of cardiovascular disease as well as distinct immune responses between sexes. Thus, the aim of this thesis was to establish if the spleen is necessary in maintaining cardiovascular homeostasis (i.e., does the chronic absence of the spleen lead to the development of cardiovascular disease or dysfunction?) and to determine if there are sex differences in contributions of the spleen to cardiovascular physiology, using animal models of splenectomy. We hypothesize that 1) the long-term loss of the spleen causes the development of cardiovascular dysfunction or disease states emulating the epidemiological studies and 2) the manifestation of cardiovascular dysfunction or disease differs between males and females. Here we demonstrate that following the removal of the spleen, a heart failure with preserved ejection fraction (HFpEF) like syndrome develops, characterized by cardiac hypertrophy, fibrosis, and diastolic dysfunction along with comorbidities (i.e., hypertension, obesity, glucose intolerance, anemia) by one year. Females presented with similar functional impairments, but in the absence of overt fibrosis and a divergent cardiac macrophage profile. Acutely, splenectomy was associated with a reduction in anti-inflammatory macrophages followed by cardiac fibrosis, hypertrophy and diastolic dysfunction. The data presented in this thesis identifies splenectomy as a new model of HFpEF, a condition without effective therapies. Furthermore, it identifies inflammation as a potential common underlying mechanism of HFpEF. This work establishes the spleen as important in the homeostatic maintenance of cardiovascular function and structure.
Date: 2020-05-02
Rights: Attribution-NonCommercial 4.0 International
Terms of Use: All items in the Atrium are protected by copyright with all rights reserved unless otherwise indicated.
Embargoed Until: 2022-05-01

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Attribution-NonCommercial 4.0 International Except where otherwise noted, this item's license is described as Attribution-NonCommercial 4.0 International