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Description
The objective of this study was to examine the potential effects of long term hormone replacement therapy on cardiovascular autonomic nervous system responses to laboratory social stressors. The participants were 38 postmenopausal women, 18 using estrogen and progesterone hormone replacement therapy for at least 2 years and 20 control participants without hormone replacement therapy. All women completed orthostasis (standing and sitting), then speech and math tasks (speech and math were counterbalanced). Cardiovascular measures of sympathetic nervous system (pre-ejection period, PEP) and parasympathetic nervous system (respiratory sinus arrhythmia, RSA) along with heart rate were collected throughout all periods (baseline, orthostasis, and stressors). For orthostasis, results of mixed analyses of variance (ANOVAs) showed expected period effects for heart rate, RSA and PEP, but no group or group by period interaction was significant. For the psychological stressors, period main effects were significant for all three variables, suggesting that the tasks were effective at inducing stress. Also, there was a significant interaction between group and period for RSA, demonstrated by greater decrease during the psychological stressor period in the group using HRT. The interactions between group and period for heart rate and PEP were non-significant. These findings support the notion that HRT may slow age-related decreases in parasympathetic responsiveness. Furthermore, changes in vagal reactivity in relation to use of HRT appear to occur within mechanisms involving response and coping with psychological stressors, rather than mechanisms that accommodate basic physiological task such as orthostasis.
ContributorsValancova-Acevedo, Katarina (Author) / Burleson, Mary H. (Thesis advisor) / Roberts, Nicole A. (Committee member) / Newman, Matt L. (Committee member) / Arizona State University (Publisher)
Created2013
Description
Cardiovascular disease (CVD) remains the leading cause of mortality, resulting in 1 out of 4 deaths in the United States at the alarming rate of 1 death every 36 seconds, despite great efforts in ongoing research. In vitro research to study CVDs has had limited success, due to lack of biomimicry and structural complexity of 2D models. As such, there is a critical need to develop a 3D, biomimetic human cardiac tissue within precisely engineered in vitro platforms. This PhD dissertation involved development of an innovative anisotropic 3D human stem cell-derived cardiac tissue on-a-chip model (i.e., heart on-a-chip), with an enhanced maturation tissue state, as demonstrated through extensive biological assessments. To demonstrate the potential of the platform to study cardiac-specific diseases, the developed heart on-a-chip was used to model myocardial infarction (MI) due to exposure to hypoxia. The successful induction of MI on-a-chip (heart attack-on-a-chip) was evidenced through fibrotic tissue response, contractile dysregulation, and transcriptomic regulation of key pathways.This dissertation also described incorporation of CRISPR/Cas9 gene-editing to create a human induced pluripotent stem cell line (hiPSC) with a mutation in KCNH2, the gene implicated in Long QT Syndrome Type 2 (LQTS2). This novel stem cell line, combined with the developed heart on-a-chip technology, led to creation of a 3D human cardiac on-chip tissue model of LQTS2 disease.. Extensive mechanistic biological and electrophysiological characterizations were performed to elucidate the mechanism of R531W mutation in KCNH2, significantly adding to existing knowledge about LQTS2. In summary, this thesis described creation of a LQTS2 cardiac on-a-chip model, incorporated with gene-edited hiPSC-cardiomyocytes and hiPSC-cardiac fibroblasts, to study mechanisms of LQTS2.
Overall, this dissertation provides broad impact for fundamental studies toward cardiac biological studies as well as drug screening applications. Specifically, the developed heart on-a-chip from this dissertation provides a unique alternative platform to animal testing and 2D studies that recapitulates the human myocardium, with capabilities to model critical CVDs to study disease mechanisms, and/or ultimately lead to development of future therapeutic strategies.
ContributorsVeldhuizen, Jaimeson (Author) / Nikkhah, Mehdi (Thesis advisor) / Brafman, David (Committee member) / Ebrahimkhani, Mo (Committee member) / Migrino, Raymond Q (Committee member) / Plaisier, Christopher (Committee member) / Arizona State University (Publisher)
Created2021