Browsing by Subject "cardiovascular"

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    Defining Mechanisms of Inflammation and Fibrosis In Cardiac Valve Disease
    (2019-05) Meier, Lee
    Cardiovascular disease (CVD) has been the leading cause of death for over a century and it will continue to be for the foreseeable future. While it has long been hypothesized that inflammation and the immune system play contributory roles in CVD initiation and progression, only recently was confirmatory evidence acquired from a large-scale clinical trial in humans. Thus, despite the existence of significant scientific and clinical efforts invested in understanding immunopathology in CVD, only recently has definitive evidence in support of this line of reasoning been acquired. Despite numerous scientific advances in recent years, our understanding of CVD and the role of inflammation therein remains limited. To date, no FDA approved drugs exist that specifically target aspects of inflammation in CVD despite the breadth of scientific data that underlies its importance. As such, continued investigation of the cellular and molecular mechanisms that govern CVD initiation and progression are needed. In this dissertation I seek to expand the scientific and clinical community’s understanding of the role for inflammation in the development of cardiac valve disease, a subset of CVD and a significant contributor to morbidity and mortality worldwide. Firstly, Chapter 1 provides an overview of cardiovascular structure and normal physiology. Secondly, Chapter 2 provides a brief overview of various forms of acquired CVD including atherosclerotic CVD, with emphasis on valvular heart disease (VHD). Therein, I include an introductory discussion of the role of inflammation in acquired CVD development. Thirdly, Chapter 3 provides a discussion of the current understanding of antibodies with specificity to self-epitopes (i.e. autoantibodies) during the initiation and progression of CV inflammation and its downstream chronic consequences on CV function. Therein, I provide motivation for studying the role of autoantibodies in CVD initiation and progression and provide insight into the current understanding of how autoantibodies interface with elements of the circulatory system to further CVD progression. As our animal model of systemic inflammation and cardiac valve disease is driven by autoantibodies, the discussion in this review provides a framework for the experimental studies that follow in later chapters of this dissertation. Chapter 4 demonstrates that discrete population of mononuclear phagocytes (MNP) are critical for MV inflammation and fibrosis. Therein, I provide evidence that MNPs are necessary for disease initiation and progression and are critical orchestrators of MVD through cytokine secretion in response to activating FcγR signaling. Downstream of MNP cytokine production, activation of the MV interstitium drives recruitment of additional inflammatory cells. On a chronic timescale, MV fibrosis results. Finally, I provide evidence for upregulation of similar pathways in samples acquired from human inflammatory MVD. Chapter 5 expands on the observations set forth in Chapter 4, and provides additional mechanistic clarification of the role for MNPs during the initiation and progression of MV inflammation and fibrosis in K/B.g7 mice and in humans. Firstly, I demonstrate that type-2 inflammation is required for disease in K/B.g7 mice and acts through multiple levels to orchestrate both systemic inflammation and cardiac valve-localized inflammation and fibrosis. Within the context of MV disease, I provide evidence that IL-13 (and not IL-4) is an important aspect of valve fibrosis. Next, I demonstrate a role for apoptotic cell accumulation and expression of the ‘don’t eat me’ signal, CD47, during the initiation and progression MVD. I show that blockade of this immune checkpoint enhances phagocytic cell clearance, and decreases MNP production of TNF, IL-6, and IL-13. The MVD dampening effect is seen when CD47 blockade is conducted both preventatively and therapeutically, thereby underscoring the central role of this pathway in disease progression. Lastly, I provide evidence for upregulation of these pathways in human RHD samples, again providing evidence for the translational potential these results hold. Finally, Chapter 6 provides preliminary evidence that a hallmark of MV inflammation in K/B.g7 mice is induction of endothelial-mesenchymal transition (EndoMT). Therein, I show that MV endothelial cells upregulate CD47 during pathological EndoMT and that this process is attenuated in the setting of CD47 checkpoint blockade. Additional work is needed to better clarify the role for EndoMT in development of MV inflammation and fibrosis, however, it is tempting to speculate about a putative pro-fibrogenic role for endothelial-derived mesenchymal cells during the course of chronic MV inflammation and fibrosis. Collectively, the results presented here provide substantial mechanistic insight into the underlying cellular and molecular pathways that contribute to cardiac valve fibrosis in the setting of chronic, autoimmune inflammation. These studies were the first to definitively implicate myeloid cells in the fibrotic remodeling of the MV and, in doing so, identified nearly ten putative therapeutic targets for exploration in human disease. Future investigation will involve more definitive identification of specific cell population(s) that drive disease progression and their individual developmental origins.
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    Extracranial Systemic Embolic Events in a Nationally Representative Discharge Database
    (2020-12) Adam, Terrence
    Introduction: Systemic emboli affect the brain and extracranial sites resulting in ischemic events with high morbidity and mortality. Extracranial systemic embolic events (ESEEs) frequently affect aortic, iliac, mesenteric, kidney, upper and lower extremity sites. The understanding of factors associated with ESEEs is limited, but atrial fibrillation is likely a major ESEE risk factor. Methods: A retrospective cross-sectional study was completed using the largest publicly available all-payer inpatient care database, the National Inpatient Sample (NIS). All adult NIS discharges were included and atrial fibrillation and ESEE subgroups identified for analysis. Descriptive statistics, multivariable logistic and linear regression were used to assess the association between ESEEs and atrial fibrillation. Other outcomes included inpatient mortality, length of stay and total hospital charges. Results: Hospital discharges with ESEEs had higher inpatient mortality (10.3% vs 2.2%), longer length of stay (6 days vs 3 days) and higher total charges ($86,888 vs $30,737) than non-ESEE discharges. The discharges with concurrent atrial fibrillation were more likely to experience ESEEs, with the majority of events involving lower limbs, mesentery and kidneys. After adjustment for demographic, geographic and institutional factors, ESEEs remained associated with increased mortality, higher total hospital charges and longer length of stay. Discussion: ESEEs with concurrent atrial fibrillation were associated with high inpatient mortality, total hospital charges and longer length of stay. Overall, among all NIS discharges, the most frequent ESEE sites were the lower extremity, mesentery and iliac regions.
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    Infection and Cardiovascular Disease: The Atherosclerosis Risk in Communities Study
    (2017-07) Cowan, Logan
    Infection has been identified as both a chronic and acute risk factor of cardiovascular disease (CVD). Despite the growing body of evidence, additional research elucidating the relationship between infection and CVD is needed. This dissertation employs longitudinal data from the Atherosclerosis Risk in Communities (ARIC) study, the Longitudinal Investigation of Thromboembolism Etiology (LITE) ancillary study, the Dental-ARIC (D-ARIC) ancillary study, and the corresponding ARIC study participant Centers for Medicare and Medicaid Services (CMS) data to examine the relationship between infection and CVD. In the first manuscript we assessed the longitudinal relationship between self-reported periodontal disease and clinical periodontal disease and incident venous thromboembolism (VTE). Self-reported periodontal disease was associated with 30% higher VTE risk that remained significant or borderline significant after adjustment. Crude associations between clinical periodontal disease classifications were attenuated with adjustment and were no longer significant. In the second manuscript we assessed the longitudinal relationship between history of endodontic therapy (ET) and incident coronary heart disease (CHD), ischemic stroke, heart failure, and VTE. We found no significant associations between self-reported history of ET and any of our outcomes of interest that remained after adjustment. In the final manuscript we used a case-crossover study design to evaluate infection as a potential trigger of CHD, ischemic stroke, and VTE. Infection was associated with higher odds of CHD, stroke, and VTE up to 90 days following the infection. The association between infection and CVD/VTE was graded such that the infection-CVD/VTE association was highest immediately following the infection and decreased as the time since the infection increased. Generally, outpatient infection was a weaker CVD/VTE trigger compared to all infections. Further research is needed to pinpoint if periodontal disease is independently associated with VTE risk and if periodontal prevention and treatment could reduce VTE risk. Our results do not support an independent association between endodontic therapy and CVD or VTE. The results of the third manuscript provide evidence in support of our hypothesis that infection is a CVD/VTE trigger. Patients with an infection who are at elevated risk of CVD should be considered potential candidates for CVD prophylaxis during and immediately after infection to reduce the otherwise elevated CVD/VTE risk.