MA, Kent State University, 2024, College of Arts and Sciences / Department of Psychological Sciences

Heart disease (HD) remains the leading cause of death (LCOD) in America. Despite public health campaigns, awareness of this fact decreased from 65% in 2009 to 44% in 2019 among women over the age of 25 and was only 10% for women aged 15-24. Declines were greater for women younger than 65, Hispanic, and Black. In 2021, the National Heart, Lung, and Blood Institute (NHLBI) issued a notice of special interest in promoting cardiovascular health earlier in life. The current cross-sectional study compared awareness of HD as the leading cause of death (LCOD) and greatest health problem among Black and White women and men aged 20-39. Given that Black women have a higher risk of HD than White women, we were particularly interested in possible race and sex differences in HD awareness among young adults. We hypothesized that women would be less aware that heart disease is the LCOD and the greatest health problem for people of all ages. We also expected Black women would be less likely to identify heart disease as the LCOD and the greatest health problem and would report lower levels of motivation to improve their CVH and reduce their risk for CVD compared to young White women. The online survey was conducted using QualtricsXM panels. Respondents (n = 404) included Black women (25.0%, 29.0 ± 6.1 yrs), White women (24.3%, 26.4 ± 4.3 yrs), Black men (24.8%, 30.6 ± 5.2 yrs), and White men (25.9%, 32.8 ± 4.5 yrs). Correct identification of HD as the LCOD was similar for women and men whether choosing from a list (24.1% vs. 26.8%) or by ranking the top 5 LCODs (17.6% vs. 20.0%) [χ2(1, 404), p ≥ .53]. Whereas 31.7% of males correctly identified HD as the LCOD for people whose birth sex is male, only 15.6% of females correctly identified HD as the LCOD death in people whose birth sex is female [χ2(1, 404) = 14.5, p < .001]. Likewise, only 13.6% of females correctly identified HD as the greatest health problem for people whose birth sex is female, compared to 29.3% of males that cor (open full item for complete abstract)

Committee: Joel Hughes (Advisor) Subjects: Psychology; Public Health; Sociology

PhD, University of Cincinnati, 2024, Medicine: Pathobiology and Molecular Medicine

Obesity is defined as an excess of body fat and is driven by imbalances between energy consumption and energy expenditure that results in the storage of excess energy within adipose tissue. Excess body fat enhances the risk of developing several obesity-associated complications which ultimately contribute to cardiometabolic disease progression. Considering the relationship between obesity and cardiovascular disease, the development of therapies that address the root cause of excess adiposity are of major interest. In addition to this pursuit, an enhanced understanding of the mechanisms by which adipose tissue communicates to maintain cardiovascular function is warranted. Given that obesity is driven by an imbalance in energy availability and utilization, a major therapeutic goal is the sustainable enhancement of energy expenditure. Brown adipose tissue (BAT) thermogenesis represents an inducible, energy expending pathway that has been emphasized as a potential obesity therapeutic. Our lab recently identified RNA binding protein, Human Antigen R, as a regulator of BAT thermogenesis through the cycling of intracellular calcium. In addition, preliminary evidence from our lab showing an inverse correlation between subcutaneous white adipose tissue (scWAT) HuR expression and left ventricular ejection fraction suggests a role for HuR in the adipose tissue-myocardium signaling axis. Considering the potential for HuR to modulate both BAT calcium-driven thermogenesis and adipose tissue-mediated cardiovascular function, our overall goal for this work was to determine the involvement of HuR in coordinating adipose tissue energy and endocrine functions. Our first objective was to identify the mechanistic role for HuR in brown adipose tissue calcium-driven thermogenesis where we observed a reduction in adrenergic-stimulated cytosolic calcium and cellular heat in HuR-deficient brown adipocytes. We identified a direct binding relationship between HuR and RyR2 mRNA that is (open full item for complete abstract)

Committee: Michael Tranter Ph.D. (Committee Chair); Shailendra Patel (Committee Member); Kristin Stanford Ph.D. (Committee Member); Jason Winnick (Committee Member); Evangelia Kranias Ph.D. (Committee Member); David Hui Ph.D. (Committee Member); Phillip Owens Ph.D. (Committee Member) Subjects: Pathology

Doctor of Philosophy, Case Western Reserve University, 2023, Biomedical Engineering

Methods for non-invasively assessing coronary artery disease (CAD), the leading cause of mortality and morbidity worldwide, are often inadequate. Among the non-invasive imaging methods, only CT allows one to reliably visualize and quantify the blood vessel lumen using coronary computed tomography angiography (CCTA). My goal is to develop an accurate and practical solution for quantitative cardiac CT perfusion (CCTP). Using CCTA and CCTP, one can identify the presence of an obstructive lesion and directly determine its impact on myocardial blood flow (MBF). In addition, one can uniquely identify low MBF on myocardium and no obstructions in major arteries, indicating the presence of microvascular disease (MVD), a rising concern in cardiology, especially due to its prevalence in diabetes and women. Four projects leading to and using quantitative CCTP are described. First, two scanner-independent, calibration-free, image-based automatic beam-hardening correction algorithms (ABHCs) were developed and compared to other existing correction methods by evaluating artifacts and MBF. Our AHBCs improved the HU value and final MBF estimation results in a digital dynamic anthropomorphic phantom and preclinical porcine experiments that included gold standard virtual mono-energetic images free of beam hardening. Second, the simple linear iterative clustering algorithm with robust perfusion quantification (SLICR) method was developed to reduce the effects of noise and obtain better MBF estimates. In the case of high noise (50% standard x-ray dose level), SLICR improved both standard deviations and means as compared to a singular value decomposition-model independent method with spatio-temporal bilateral filter (101 ± 12 vs. 54 ± 24 mL/min-100g, p < 0.05, actual MBF = 100 mL/min-100g). It gave MBF estimates of 101±6 mL/min-100g for an actual MBF of 100 mL/min-100g, at standard x-ray dose levels and gave estimates resistant to increases in noise. SLICR also greatly reduced computati (open full item for complete abstract)

Committee: Satish Viswanath (Committee Chair); Sanjay Rajagopalan (Committee Member); Raymond Muzic Jr (Committee Member); David Wilson (Committee Member) Subjects: Biomedical Engineering

Bachelor of Science (BS), Ohio University, 2023, Translational Health

Objectives: The study evaluated the effectiveness of an enhanced West Virginia FARMacy program designed to prescribe healthy food and education to modify multiple cardiovascular disease risk factors in participants who were at risk for or previously diagnosed with a chronic disease. Methods: Participants met weekly for 2-hours where they were provided with locally sourced produce coupled with education and group wellness coaching focused on plant-based food, cooking, and physical activity. Baseline data consisted of demographics, a readiness for change assessment, height, weight, resting blood pressure, lipid panel and glycosylated hemoglobin (HbA1c). These were repeated twice throughout the program. Data were analyzed for change over time using repeated measures ANOVAs, t-tests, and F-tests and effect size. Results: The sample consisted of 33 participants (Mean±SD: 62.2+11.7 y; range: 23 to 79 y; 81% females (n= 27). Significant improvements from baseline were observed in systolic blood pressure (↓ 9.4%; p = 0.006), triglycerides (↓ 16.9%; p = 0.04), dark green vegetables ( ↑ 84.7%; p < 0.001), and colorful vegetables ( ↑ 73.5%; p = 0.002). Between baseline and timepoint 3, BMI decreased ~2 kg/m2, improving the overall group weight classification from the obese to overweight classification (p < 0.001). While HbA1c did not significantly change throughout the program, it had a large effect size (0.96) between timepoint 2 and 3. Discussion: These results suggest that FARMacy is an effective program to reduce CVD RFs in a rural Appalachian population using lifestyle interventions.

Committee: David Drozek, DO (Advisor); Cheryl A. Howe, PhD, FASCM (Advisor) Subjects: Health Education

Master of Science in Biomedical Sciences (MSBS), University of Toledo, 2021, Biomedical Sciences (Bioinformatics and Proteomics/Genomics)

Advances in machine learning (ML)-based techniques has popularized wide applications of artificial intelligence (AI) in various fields ranging from robotics to medicine. In recent years, there has been a surge in the application of AI to research in cardiovascular medicine, which is largely driven by the availability of large-scale clinical and multi-omics datasets. Such applications are providing a new perspective for a better understanding of cardiovascular disease, which could be used to develop novel diagnostic and therapeutic strategies. For example, studies have shown that ML has a substantial potential for early diagnosis of different types of cardiovascular diseases, prediction of adverse disease outcomes such as heart failure, and development of newer and personalized treatments. In chapter 1, I present a review of the current literature on a wide range of AI applications, including machine learning, reinforcement learning and deep learning, in cardiovascular medicine. The contents of this chapter were peer-reviewed and accepted as a review article in Comprehensive Physiology. My contribution to this publication was to collect literature, read, compose various sections and compile the review for a comprehensive presentation. I share first-co-authorship with Sachin Aryal on this publication. While we were undertaking the work described in Chapter 1, the Physiology branch of the Joe laboratory had discovered gut microbiota as new entrants into the field of cardiovascular medicine. Specifically, the gut microbiome (which represents the genomes of gut microbiota) is now recognized as an important feature in hypertension, which is the single largest risk factor for all cardiovascular illnesses. Risk prediction for cardiovascular disease, as described in Chapter 1, is possible with machine-learning, but such machine-learning did not use microbiome as a feature. Therefore, it was intriguing for us to test the hypothesis that the gut microbiome represents a new f (open full item for complete abstract)

Committee: Bina Joe Dr. (Advisor); Robert Blumenthal Dr. (Committee Member); Xi Cheng Dr. (Committee Member) Subjects: Bioinformatics; Biomedical Research

Master of Sciences, Case Western Reserve University, 2021, Biology

The medical device industry is diverse, dynamic, and above all, highly competitive. This study investigates the role of competitive intelligence research in the development of an effective business strategy for Centerline Biomedical Inc., a mid-stage medical device start-up commercializing a novel endovascular navigation technology. Using a variety of secondary research sources, a competitive intelligence analysis was conducted, focusing on vascular navigation and imaging. Seven industry players were identified as competitors to Centerline Biomedical based on their product pipelines and future initiatives. Using this data, potential strategies for directing Centerline Biomedical's growth were explored. In order to manage sources of competition and more quickly achieve the organization's goals of establishing critical mass, expanding their product portfolio, and planning for a successful exit, a strategic partnership with a leading industry player is proposed and described.

Committee: Christopher Cullis Dr. (Committee Chair); Mark Willis Dr. (Committee Member); Leena Chakravarty Dr. (Committee Member); Philip Rackliffe (Committee Member) Subjects: Medical Imaging; Medicine

MS, University of Cincinnati, 2019, Medicine: Clinical and Translational Research

Background Treatment with targeted pulmonary vasodilator therapy has been shown to benefit patients with pulmonary hypertension (PH), but identifying characteristics that predict treatment response has been challenging. Cardiac Magnetic Resonance Imaging (cardiac MRI) is the superior noninvasive testing modality for investigating cardiac structure and function, and may have prognostic value in pulmonary hypertension patients. We sought to evaluate the role of baseline cardiac MRI in predicting clinical outcomes in treatment naive PH patients. Methods A retrospective analysis of all consecutive adults with newly diagnosed treatment-naive PH undergoing cardiac MRI testing at a single center was performed. Cox proportional hazards models were constructed to assess the relationship between clinical and demographic information (including baseline cardiac MRI testing results) and clinical worsening. Results A total of 38 patients were included in the final analysis, of which 12 (32%) experienced the primary outcome of clinical worsening during the study period. In the multivariable models, cardiac MRI testing had significant and independent value in predicting clinical worsening, and a combination of cardiac MRI and echocardiographic testing had a 100% specificity in identifying patients who subsequently developed clinical worsening. Conclusions In treatment-naive PH patients, baseline cardiac MRI testing may have an important role in predicting therapeutic response and identifying those at risk of treatment failure. These results support the role of cardiac MRI testing in these patients, and further investigation is warranted

Committee: Aimin Chen Ph.D. (Committee Chair); Francis McCormack M.D. (Committee Member); Marepalli Rao Ph.D. (Committee Member) Subjects: Surgery

Doctor of Philosophy (PhD), University of Toledo, 2018, Biomedical Sciences (Molecular Medicine)

Insulin resistance has long been considered to play a crucial role in the pathophysiology of metabolic syndrome that is the leading cause of mortality and morbidity worldwide. Metabolic diseases consist of a group of metabolic abnormalities that increase the risk of health problems, such as type 2 diabetes (T2D) and cardiovascular disease. Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and metabolic syndromes. It is the fastest growing cause of liver dysfunction. Its progressive form nonalcoholic steatohepatitis (NASH) is associated with hepatic fibrosis that can develop into cirrhosis. In addition, there is a growing body of evidence that among risk factors that promote atherosclerosis, metabolic syndrome is a potent predictor of cardiovascular events. Insulin resistance seems to play a major role in the pathophysiology of atherosclerosis in relation with metabolic syndrome. Given that patients with NAFLD/NASH are at a high risk to develop atherosclerosis; these two diseases may share some pathology. However, precise molecular mechanisms underlying the pathogenesis and progression of these diseases are not well understood. Thus studying the molecular link between them would pinpoint sites of more effective pharmacologic interventions. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a protein that is markedly reduced in the liver of patients with NASH, promotes insulin clearance to regulate insulin action. Whether or not CEACAM1 links hyperinsulinemia to NAFLD/NASH and atherosclerosis still needs to be determined. CEACAM1 enhances the rate of uptake of the insulin-receptor complex into the clathrin-coated vesicles of hepatocytes. It also plays a major role in mediating the negative acute effect on fatty acid synthase (Fasn) activity. As such, CEACAM1 regulates insulin and lipid metabolism. Mice with global null mutation of CEACAM1 (Cc1–/–) display hyperinsulinemia resulting from impaired insulin clearance, insulin resist (open full item for complete abstract)

Committee: Sonia Najjar PhD (Committee Chair); Guillermo Vazquez PhD (Committee Member); Jennifer Hill PhD (Committee Member); Rajesh Gupta MD (Committee Member); David Kennedy PhD (Committee Member); Steven Haller PhD (Committee Member) Subjects: Biomedical Research

Doctor of Philosophy, The Ohio State University, 2017, Psychology

Individuals endorsing higher rates of delay discounting (DD) tend to discount the value of future rewards, such that the perceived value of the future reward, though larger than an immediate reward, is viewed as less valuable. In turn, DD is associated with engaging in poor health behaviors, such as unhealthy diet and low levels of physical activity, both of which may increase risk of developing cardiovascular disease (CVD). Individuals with elevated genetic risk for CVD and higher rates of DD, are likely to be especially vulnerable to developing CVD. This randomized controlled study examined rates of DD among young adults with a family history (FH) of early-onset CVD (i.e., adults with higher genetic risk for CVD; FH+) and without a FH of CVD (FH-). Associations of DD, perceived CVD risk, physical activity, dietary sodium and lipid intake, as well as health behavior intentions were assessed before, immediately following, and one week after a standard educational intervention. In addition, FH was evaluated as a moderator of these associations. High rates of DD were hypothesized to correlate with sodium and lipid consumption, and negatively correlate with perceived risk of developing CVD, level of physical activity, and intention to engage in healthy behaviors. Further, it was hypothesized that FH+ participants randomized to the experimental condition would report greater reductions in DD, sodium and lipid intake, and increases in physical activity, perceived disease risk, and health behavior intentions, compared to FH- participants in the experimental condition, and participants in the control condition. Fifty-four FH+ and 60 FH- adults between the ages of 18 and 40, with no personal history of CVD were randomized to view either an educational video about CVD, or a control educational video. Questionnaires assessed perceived risk of developing CVD, intention to engage in health behaviors, lipid and sodium intake, as well as physical activity. DD was assessed with (open full item for complete abstract)

Committee: Charles Emery PhD (Advisor); Melissa Buelow PhD (Committee Member); Julian Thayer PhD (Committee Member) Subjects: Psychology

Doctor of Philosophy, The Ohio State University, 2016, Biomedical Engineering

Endothelial cells (ECs) line the inside of blood vessels and are constantly exposed to fluid mechanical forces from the flow of blood over their surface and the motion of the vessel wall. These forces, under physiological conditions, are transduced into intracellular signals that maintain vascular health and reduce the risk of cardiovascular disease. An extremely important signal in response to shear stress is in the form of intracellular calcium concentration ([Ca2+]i) oscillations. Ca2+ is a ubiquitous second messenger and is involved in a large number of intracellular signaling cascades including those that regulate nitric oxide production (a potent vasodilator that plays a significant role in maintaining vascular health). In addition, mitochondrial Ca2+ overload leads to cell apoptosis (programmed cell death) due to the release of cytochrome c from the inner mitochondrial membrane which activates a series of caspases that leads to cell death. Ca2+ may enter the EC across the plasma membrane, or it may be released from the intracellular stores (the endoplasmic reticulum (ER) and the mitochondria). The [Ca2+]i is approximately 10-100 nM under basal conditions, while the extracellular [Ca2+] is about 2 mM. This creates a strong driving force for Ca2+ transport across the plasma membrane into the cytosol. Inside the cell, the ER contains ~75% of the intracellular Ca2+ and has one major efflux mechanism, the inositol 1,4,5 trisphosphate receptor (IP3R) and one major Ca2+ influx pathway, the sarco/endoplasmic reticulum ATP-ase (SERCA). The mitochondria sequester the majority of the remaining 25% of intracellular Ca2+ and have one major Ca2+ influx mechanism, the mitochondrial Ca2+ uniporter (MCU), and one major Ca2+ efflux pathway, the mitochondrial sodium (Na+)/Ca2+ exchanger (mNCX). Despite the significance of [Ca2+]i in maintaining EC and vascular health, the mechanisms modulating the shear-induced [Ca2+]i signal had yet to be determined. By using the Ca2+-sens (open full item for complete abstract)

Committee: B. Rita Alevriadou PhD (Advisor); Thomas Hund PhD (Committee Member); Jay Zweier MD (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2015, Public Health

Cardiovascular disease (CVD) and cancer, leading causes of morbidity and mortality in the U.S., share modifiable sources of risk. Health disparities, which are differences in the incidence, prevalence, mortality and burden of disease that should not exist, are influenced by wide-ranging social determinants of health. This research sought to address the need for improved understanding of the status and social determinants of mutual sources of CVD and cancer risk among two U.S. populations facing health disparities, Puerto Ricans living in the contiguous U.S. and residents of Appalachia, using The American Heart Association's Life's Simple 7 of Cardiovascular Health (LS7) metric and data from the Boston Puerto Rican Health Study (BPRHS) and Appalachian Community Cancer Network (ACCN). LS7 includes well-defined poor, intermediate and ideal levels of smoking, body mass index (BMI), physical activity, diet, blood pressure, total cholesterol and plasma glucose, modifiable behaviors and factors associated with CVD and cancer. The goals of this research were to: (1) quantify and compare LS7 across BPRHS and ACCN study participants and a nationally representative sample of civilian, non-institutionalized non-Hispanic whites from the National Health and Nutrition Examination Survey (NHANES), and (2) independently assess the relationship between geographic food access and LS7 healthy diet score among BPRHS and ACCN study participants. There were significant differences in the distribution of several LS7 components and overall LS7 score between BPRHS and ACCN study participants, BPRHS and NHANES participants, and ACCN study and NHANES participants. Results suggest smoking, BMI, and plasma glucose warrant further investigation among BPRHS participants and BMI and blood pressure warrant further investigation among ACCN study participants. Diet was also identified as a risk behavior for prioritization among BPRHS and ACCN study participants since <=1% of each research sample (open full item for complete abstract)

Committee: Electra Paskett (Committee Chair); Randi Foraker (Committee Member); Michelle Kaiser (Committee Member); Abigail Shoben (Committee Member) Subjects: Epidemiology; Public Health

Master of Science, The Ohio State University, 2015, Kinesiology

Tools for the functional assessment of cardiovascular fitness are needed to establish animal models of dysfunction and the effects of novel therapeutics. Currently, exercise assays are widely published; however, they have limited sensitivity for assessing the cardio-metabolic phenotype of mice. In human research, the graded maximal exercise test (GXT) is a gold standard diagnostic for measuring cardiovascular function. Present published testing methods in mice use set inclination and progressive increases in speed until exhaustion (PXT); thus lacking characteristics of the GXT. We developed a GXT test that allows for assessment of cardiovascular fitness in metabolic and genetic models of cardiovascular dysfunction; as well as in healthy mice. The results of comparison between this method and the PXT revealed that only the GXT test provides sensitive, quantitative, parameters for diagnosing and monitoring cardiovascular, metabolic and pulmonary function in mouse models.

Committee: Ouliana Ziouzenkova Dr. (Advisor); Brian Focht Dr. (Advisor); Denis Guttridge Dr. (Committee Member) Subjects: Kinesiology

MS, Kent State University, 2014, College of Arts and Sciences / School of Biomedical Sciences

A critical amount of reactive oxygen species (ROS) contributes to coronary blood flow (CBF) regulation; however, oxidative stress (OS) impairs CBF regulation and is elevated in diabetes. We have previously demonstrated TRPV1- dependent coupling of CBF to metabolism is disrupted in diabetic cardiomyopathy (DCM). Accordingly, we hypothesized that basal levels of H2O2 stimulate TRPV1 whereas enhanced oxidative stress desensitizes and/or deactivates TRPV1 indirectly via a mechanism involving the lipid peroxidation product 4-Hydroxy-2-nonenal (4-HNE). H2O2 caused robust dilation in control coronary microvessels (blunted in the presence of the TRPV1 inhibitor SB366791 and in TRPV1-/- vessels), suggesting H2O2 - induced vasodilation occurs in part via TRPV1. Acute exposure to H2O2 potentiates capsaicin – mediated (TRPV1 agonist) vasodilation while a prolonged exposure to H2O2 eliminates this TRPV1 – dependent response. Interestingly, coronary microvessels isolated from db/db mice exhibit diminished H2O2 – induced coronary dilation when compared to controls remaining consistent with our previous findings. Lastly, coronary microvessels isolated from control mice incubated with 4-HNE demonstrate reduced TRPV1 – dependent coronary vasoreactivity. These data suggest low levels of H2O2 can potentiate TRPV1 activation. However, increased ROS concentrations, as seen in DCM, can lead to enhanced 4-HNE levels which modulate TRPV1 and disrupt its signaling. Thus, H2O2 – mediated differential regulation of TRPV1 could provide insight into the mechanism responsible for the uncoupling of myocardial blood flow (MBF) to metabolism associated with diabetes and DCM.

Committee: Ian Bratz PhD (Advisor); William Chilian PhD (Committee Chair); Charles Thodeti PhD (Committee Member); Derek Damron PhD (Committee Member) Subjects: Biomedical Research

MS, University of Cincinnati, 2011, Medicine: Clinical and Translational Research

Resistin, a 12.5 kDa protein, is produced by inflammatory cells and is elevated in patients with chronic kidney disease (CKD). While resistin was initially thought to mediate insulin resistance, more recent attention has focused on its role in inflammation and cardiovascular disease. This cross-sectional study analyzes the association of serum resistin with clinical and demographic parameters in the CKiD cohort, a large cohort of pediatric patients with stage II-IV CKD. In univariate analyses, serum resistin levels correlated negatively with glomerular filtration rate (GFR, p < 0.01). Increased serum resistin levels were associated with elevation of inflammatory cytokines, including interleukin-6 (IL-6, p < 0.01), interleukin-10 (p < 0.01), and tumor necrosis factor-a (p < 0.01). Resistin was not associated with insulin resistance (p = 0.13) as assessed by the homeostasis model assessment of insulin resistance (HOMA-IR), although it was positively correlated with serum triglycerides (p < 0.01) and negatively correlated with high-density lipoprotein cholesterol (p < 0.01). In multivariate analysis, only GFR, IL-6, pubertal status, and HOMA-IR were significantly associated with serum resistin. HOMA-IR, however, was negatively correlated with serum resistin. This was an unexpected finding that demonstrated an association of serum resistin levels with improved insulin sensitivity. IL-6 was strongly associated with resistin in multivariate analysis, suggesting that resistin is involved in the inflammatory milieu present in CKD and therefore may represent a novel risk factor for cardiovascular disease. Future prospective data will be needed to evaluate the predictive value of resistin in cardiovascular morbidity in children with CKD.

Committee: Paul Succop PhD (Committee Chair); Mark Mitsnefes MD (Committee Member); Erin Nicole Haynes PHD (Committee Member) Subjects: Surgery

MA, Kent State University, 2011, College of Arts and Sciences / Department of Psychological Sciences

Increased sleep impairment is a common symptom of cardiovascular disease, and can contribute to difficulty with normal activities of living. One explanation for the increased sleep impairment observed in persons with cardiovascular disease is the presence of chronic, low-level inflammation. Cytokines are neuroimmunomodulating cells that can signal various physiological processes, such as sleep. Cytokines are secreted in abundance by immune cells as well as epithelial cells, and are thought to be secreted in low-levels in people with cardiovascular disease, thus leading to sustained inflammation. This study investigated the association between cytokine levels as well as t-helper type 1 (Th1) to t-helper type 2 (Th2) ratio and factors of sleep in patients who were diagnosed with cardiovascular disease. Ninety-six participants recruited from a cardiovascular rehabilitation program were asked to complete the Pittsburgh Quality Sleep Index (PSQI) and to undergo a venous blood draw within the first two weeks of rehabilitation. Analysis of Covariance (ANCOVA) revealed that participants who reported an inability to get to sleep within 30 minutes had higher blood plasma concentrations of IL-10 (M = 1.52, SD = 0.54 versus M = 1.24, SD = 0.46, F (1,69) = 4.48, p = .038) and TNF-α (M = 2.14, SD = .61 versus M = 1.78, SD = .71, F (1, 69) = 4.70, p = .034). In addition, TNF-α to IL-4 ratio in blood plasma was increased in participants reporting an inability to fall asleep within 30 minutes when compared to participants who reported that they fell asleep within 30 minutes (M = 1.40, SD = .572 versus M = 1.16, SD = .555, F (1, 63) = 5.81, p = .019). Multiple regression analysis revealed that IFN-γ was positively correlated with sleep duration (B = .466, p = .038). In conclusion, this study provides evidence that sleep impairment may be a result of chronic inflammation in patients with heart disease. Future research is indicated to understand the causal relationship between sleep an (open full item for complete abstract)

Committee: Joel Hughes PhD (Advisor); John Gunstad PhD (Committee Member); David Riccio PhD (Committee Member); Kathryn Kerms PhD (Committee Member) Subjects: Psychobiology

Master of Sciences, Case Western Reserve University, 2009, Clinical Research

Patients with chronic kidney disease (CKD) are at high risk for coronary heart disease (CHD). The performance of the Framingham equation, used to assess CHD risk, is consistently worse in minority subjects and those with CKD. The purpose of this study was to evaluate the addition of race and CKD to the traditional risk factors in the Framingham equation. Two CHD prediction models were developed in subjects from ALLHAT: the first included only traditional Framingham variables, the second added CKD and stratified by race. The performance of these models was evaluated in subjects from the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. In both cohorts, the new models' performance was poor and was significantly worse than the traditional Framingham equation. In conclusion, the current results do not support the addition of race and CKD to a model including traditional Framingham risk factors.

Committee: Barbara Cromer M.D. (Committee Chair); Mahboob Rahman M.D. (Committee Member); Denise Babineau Ph.D. (Committee Member) Subjects: Epidemiology; Health Care

PHD, Kent State University, 2025, College of Arts and Sciences / School of Biomedical Sciences

Cardiovascular disorders remain the leading cause of morbidity and mortality worldwide, with atherosclerosis as the predominant underlying pathology. In individuals with Metabolic Syndrome (MetS), which encompasses conditions such as obesity, diabetes, dyslipidemia, and hypertension, the development of atherosclerosis is accelerated. Vascular smooth muscle cells (VSMCs) play a pivotal role in atherosclerotic plaque formation through phenotypic switching—a process influenced by various extracellular factors, including TSP1. TSP1, a matricellular glycoprotein, has emerged as a key mediator of vascular inflammation, remodeling, and cell behavior. However, its precise role in VSMC differentiation and atherosclerosis in the context of MetS remains unclear. The significance of my dissertation lies in addressing the critical knowledge gap surrounding TSP1's role in VSMC phenotypic modulation within atherosclerotic lesions, particularly under the compounded metabolic stresses of MetS. The goal of this study was to elucidate the effect of TSP1 on VSMC behavior and plaque development. We specifically investigated the link between TSP1 expression, atherosclerosis, and SMC differentiation in MetS and the regulatory role of smooth muscle-specific TSP1 in SMC phenotypic changes in diabetes and the molecular pathways involved. We found that agouti KKAy+/-ApoE-/- mice (MetS) exhibited pronounced metabolic disturbances, including significant increases in body weight, non-fasted blood glucose levels (>250 mg/dL), and plasma lipid levels (cholesterol and triglycerides) compared to non-agouti KKAy-/-ApoE-/- controls (non-MetS). Male MetS mice demonstrated severe glucose intolerance, although insulin sensitivity was unaffected across groups. Male MetS mice exhibited significantly greater lipid burden and plaque area in the aortic root associated with upregulation of TSP1 and lesser testosterone levels compared to non-MetS males. However, female MetS mice did not display the same les (open full item for complete abstract)

Committee: Priya Raman (Advisor); Mohammad Yunus Ansari (Committee Member); Jessica Ferrell (Committee Member); Vahagn Ohanyan (Committee Member) Subjects: Biomedical Research; Pharmacology

PhD, University of Cincinnati, 2024, Pharmacy: Pharmaceutical Sciences

Background: Bariatric surgery, as a pivotal intervention to treat obesity, has seen dynamic utilization trends over recent years, and the subsequent pharmacological implications, particularly concerning statin discontinuation, hold significance. With the world grappling with the cardiovascular epidemic and its associated mortality, there's an imperative need to understand the cardiovascular outcomes post-bariatric surgery, especially when linked with discontinuation of critical medications like statins. Aims: This dissertation aimed to delineate the trends in bariatric surgery utilization and the corresponding shifts in surgical techniques in the U.S. Furthermore, it sought to understand the patterns and repercussions of statin discontinuation post-surgery, with an emphasis on discerning the risks associated with discontinuing statin therapy, particularly among patients with a history of Atherosclerotic Cardiovascular Disease (ASCVD). Methods: Comprehensive retrospective analyses were conducted utilizing the TriNetX electronic medical records network, spanning the years 2012 to 2021. The trends in bariatric surgeries were examined alongside their procedural variations. In parallel, patients on statin therapy undergoing bariatric surgery were identified, with their subsequent statin discontinuation patterns being analyzed. The consequences of such discontinuations, especially regarding ASCVD events, were also explored, taking into consideration both primary and secondary prevention cohorts. Results: There was a steady upswing in bariatric surgeries until 2018, which saw a decline during 2020 and 2021, coinciding with the COVID-19 pandemic. The surgical landscape depicted a decline in the Roux-en-Y (RYGB) procedure, substituted by an uptake in the sleeve gastrectomy (SG) procedure. Among statin therapy users, 48% of primary prevention and 34.5% of secondary prevention patients discontinued statin therapy within six months post-bariatric surgery. Alarmingly, w (open full item for complete abstract)

Committee: Ana Hincapie Ph.D. (Committee Chair); Jianfei (Jeff) Guo Ph.D. (Committee Member); Patricia Wigle Pharm.D. (Committee Member); Marepalli Rao Ph.D. (Committee Member); Alex Lin Ph.D. (Committee Member) Subjects: Pharmacy Sciences

Doctor of Philosophy, Case Western Reserve University, 2024, Biomedical Engineering

Opportunistic imaging, specifically using CT calcium scores (CTCS) and chest X-rays, has emerged as a pivotal approach in the early detection of coronary artery disease. The CTCS exam is fast and provided as a low-cost (no-cost) screening exam for cardiovascular disease. Notably, the Agatston CT calcium score stands out as the most reliable single biomarker for forecasting the occurrence of major adverse cardiovascular events (MACE). The availability of extensive databases containing CTCS and chest X-ray images with clinical outcomes facilitates comprehensive studies on cardiovascular population health. My goal is to utilize image processing and machine learning techniques in medical images to improve cardiovascular risk prediction. Four different research projects utilizing CTCS and dual energy chest X-ray are described. First, we improved the accuracy of whole-heart CT calcium scoring by refining the quantitative analysis of individual calcifications. Our approach entailed the application of Lucy-Richardson and 3D blind deconvolution techniques to standard (2.5-mm) and thin-slice (1.25-mm) CT scans on a QRM-Cardio phantom, cadaver hearts, and CARDIA study participants, with the aim of improving resolution and reducing bias in small calcification assessments. The results demonstrated that both deconvolution methods significantly improved mass score assessment on standard images, giving accuracy within 1% comparing to reference. In the CARDIA study, blind deconvolution substantially reduced bias and improved reproducibility in 21 out of 24 calcification features, suggesting its effectiveness in processing archived datasets. Overall, deconvolution techniques showed promise in mitigating bias and improving the reproducibility of individual calcification features in CT calcium score examinations. Second, we evaluated the effectiveness of physicians in identifying coronary calcifications on dual-energy chest X-rays enhanced by an advanced algorithm. Given that chest (open full item for complete abstract)

Committee: David Wilson (Advisor); Shuo Li (Committee Chair); Sanjay Rajagopalan (Committee Member); David Jordan (Committee Member) Subjects: Biomedical Engineering; Medical Imaging

Doctor of Philosophy, Case Western Reserve University, 2024, Physiology and Biophysics

Functional elastin fibers within extracellular matrix of the arterial wall facilitate passive distensibility and recoil, which is critical to maintaining blood flow. Elastin fragmentation decreases functional elastin level and is associated with aging, contributing to age-related arterial stiffening, an independent risk factor for the development of hypertension. The effects of elastin deficiency in large elastic vessels are well-known, but the impact on resistance vessels, crucial for renal perfusion and blood pressure regulation, is less explored. Furthermore, elastin insufficiency in mice is associated with elevated blood pressure, which is more pronounced in male mice than female mice when compared to their respective wild-type counterparts. However, the mechanisms underlying the sex-related differences in elastin-insufficient mice have not been explored. Using an animal model of elastin haploinsufficiency (Eln+/-), we demonstrated that loss of elastin exacerbates structural and biomechanical properties of intra-renal arteries in young Eln+/- female mice. These changes manifest as increased vascular stiffness and increased fragmentation, leading to blunted responses to increased renal perfusion pressure and impaired renal autoregulation. We further explored whether renal dysfunction contributes to hypertension in these mice and whether this relationship is modulated by ovarian hormones. Our findings establish that ovarian hormones mitigate the hypertensive phenotype in female Eln+/- mice. Though these mice exhibit impaired pressure natriuresis response, the hypertensive phenotype is not sodium-dependent. Instead, the sustained elevation in blood pressure is in part driven by increased activity of the renin-angiotensin system (RAS). Additionally, diuresis and urine concentrating ability were found to be impaired in female Eln+/- mice despite increased aquaporin 2 channel expression. Furthermore, the reduced sensitivity to vasopressin (V2) receptor blockade in Eln (open full item for complete abstract)

Committee: Patrick Osei-Owusu (Advisor); George Dubyak (Committee Chair); Jessica Wagenseil (Committee Member); Julian Stelzer (Committee Member); Jeffery Garvin (Committee Member) Subjects: Physiology