Browsing by Subject "Cardiovascular Disease"

Now showing 1 - 3 of 3
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    The Digestive Tract Microbiome and Cardiometabolic Disease: Exploring Nitric Oxide and Lipopolysaccharide Synthesis as Mechanistic Intermediates
    (2023) Bohn, Bruno
    Introduction: The role of the digestive tract microbiomes on cardiometabolic health is becoming ever clearer. However, mechanistic remain largely unexplored and methods exploring metabolic outputs are lacking. This dissertation explores a novel approach to quantify the microbiome's lipopolysaccharides (LPS) and nitric oxide (NO) producing potential, two molecules with known health effects. We investigated the association between functional metrics and cardiometabolic health among healthy individuals and heart failure (HF) patients.Methods: Cross-sectional data from adults free of cardiometabolic disease (ORIGINS) and with HF (HFM) were used. Blood pressure was measured and biomarkers or inflammation and/or endotoxemia quantified from blood serum. Oral (saliva) and/or gut microbiomes were characterized with 16S rRNA (HFM/ORIGINS) and/or metagenomic sequencing (ORIGINS). Pathway- and gene-level functional profiles were operationalized as metrics of LPS- and NO-producing potentials. Metrics were compared across sequencing approaches (ORIGINS). For each cohort, multivariable linear regression was used to explore associations between: i) blood pressure and NO-producing potential; ii) inflammation and NO-producing potential; iii) inflammation and LPS-producing potential; and iv) endotoxemia and LPS-producing potential (HFM). Results: In ORIGINS, 253 and 170 participants had 16S and metagenomic data, respectively. A modest positive association was observed between functional metrics, with more features detected through 16S methods. Metagenomic and 16S-derived NO-reducing potential metrics were linked to lower inflammation and blood pressure, respectively. No meaningful associations were observed for LPS-producing potential. In HFM, saliva and gut 16S sequencing data was available for 146 and 128 participants, respectively. No correlations were observed between gut and oral microbiomes. No meaningful associations were observed between NO-producing potential and blood pressure. Gut LPS-producing potential, but not oral, was associated with endotoxemia. Inflammation was not meaningfully linked to either functional feature. Conclusions: A novel approach to utilized microbiome functional profile metrics was explored. Findings were mixed, but highlighted the potential use of these approaches in population-based studied of the human microbiome and cardiometabolic health.
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    Empirical Determination of Vascular Smooth Muscle Cell Mechano-Adaptation
    (2017-09) Steucke, Kerianne
    Patient-specific vascular modeling seeks to provide physicians with predictive data that will enable them to make better treatment decisions and improve patient outcomes. To achieve this, these models must incorporate the mechanical response of the arterial components including the key mechanically active component - vascular smooth muscle cells (VSMCs). However, current models fail to incorporate the dynamic mechanically-induced VSMC growth and remodeling, or mechano-adaptation, behavior. Therefore, the focus of this work is to mathematically characterize VSMC mechano-adaptation using experimentally determined VSMC functional responses to perturbations in the surrounding mechanical environment. To test this hypothesis, we developed three experimental techniques and proposed two VSMC mechano-adaptation laws. First, we asked if vascular disease relevant changes in extracellular matrix mechanical properties would affect tissue-scale VSMC functional contractility. We adapted the muscular thin film assay to control the underlying substrate modulus and found that with increasing substrate modulus there is increasing VSMC contractility. Second, we asked if a simple growth law could capture single cell VSMC mechano-adaptation. To derive a VSMC mechano-adaptation law from experimental data, we engineered a chronic strain traction force microscopy method, which enabled us to apply a chronic step change in strain to micropatterned single VSMCs and measured their internal stress generation over time. We found that single VSMCs have a preferred homeostatic stress-state, referred to as target stress, that they return to if perturbed. This dynamic growth and remodeling response was described by a set of simple growth laws we termed a VSMC mechano-adaptation law. Finally, we elucidated the relationship between single VSMC mechano-adaptation and substrate modulus. To determine this law from experimental findings, we adapted the previous chronic strain traction force microscopy assay, such that the substrate modulus could be altered. We then tracked the temporal stress evolution of single VSMCs on three different substrate moduli and used those data to develop a substrate dependent VSMC mechano-adaptation law.
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    Excess Adiposity in Youth: Subclinical Cardiovascular Disease and Future Implications
    (2017-07) Fyfe-Johnson, Amber
    Excess adiposity remains a serious public health threat; 33% of U.S. adolescents are classified as having overweight or obesity. Adolescent obesity is associated with a 3.5 times higher lifetime risk of cardiovascular disease (CVD) mortality, thus subclinical CVD phenotypes such as carotid intima-media thickness (cIMT) have become widely accepted as relevant to earlier stages of CVD in youth. In the first manuscript, we developed a risk prediction model that predicted cIMT in middle adulthood using relevant CVD risk factors in adolescence. Longitudinal associations were observed between most CVD risk factors in adolescence and increased cIMT in middle adulthood; our risk prediction model poorly predicted cIMT in middle adulthood based on discrimination and calibration metrics. In the second manuscript, we contrasted longitudinal data from two bi-racial cohort studies by examining the association between CVD risk factors and cIMT in two distinct periods of life. Higher body mass index was associated with an increased cIMT in the younger cohort. In the older cohort, no association was present between body mass index and cIMT; higher systolic blood pressure was associated with increased cIMT. The American Heart Association set 2020 Strategic Impact Goals that defined CVD risk factors to include in the concept of ideal cardiovascular health (ICH). In the final manuscript, we examined the prevalence of ICH by adiposity level in youth, including severe obesity. We then generated a continuous ICH sample z-score, and examined the distribution of the ICH sample z-score by adiposity level in youth. Children with overweight/obesity and severe obesity had lower ICH sample z-scores than those with normal weight. Taken together, these three projects provide insight into the relationship between excess adiposity and subclinical CVD and cardiovascular health in youth. In addition, this dissertation considers metrics that have the potential to address excess adiposity prevention efforts in youth.