Doctor of Nursing Practice, Mount St. Joseph University , 2024, Department of Nursing

Heart failure is the leading cause of readmissions among chronic illnesses in the United States (Oh et al., 2021). Patients with chronic disease need correct knowledge and understanding about maintaining, monitoring, and managing their illness in their daily lives. However, patients with low health reading ability have a more challenging time with comprehension (Oh et al., 2021). It is imperative for acute care nursing staff to gain the ability to properly educate heart failure patients on the disease process to increase the patient's quality of life while decreasing their chance of hospital readmission. This project aimed to increase nursing knowledge related to heart failure and disease-specific education using smart-phrase technology to reduce heart failure 30-day readmission rates. After initial stakeholder meetings, staff education and training, and project implementation, the project did show a decrease in hospital admissions within the 12-week utilization period. The readmission data is under review to ensure the smart-phrase is still effective in current practice. The project achieved its goals, including improving nurse competency in heart failure and simplifying patient education.

Committee: Monica Warde (Advisor) Subjects: Health Care; Health Education; Nursing

MS, University of Cincinnati, 2024, Medicine: Clinical and Translational Research

Background: Pulmonary hypertension (PH) frequently complicates the course of patients with left heart disease (PH-LHD), and it is associated with worse clinical outcomes. Mortality calculators for PH-LHD are lacking, and it is unclear whether any risk prediction tools originally derived from other forms of PH can accurately predict outcomes in patients with PH-LHD. Methods: We retrospectively analyzed data from 161 patients with a diagnosis of PH-LHD referred to our pulmonary hypertension center from 2016 to 2022. We calculated the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) risk score and categorized patients as low, intermediate, or high-risk. We assessed survival and risk discrimination at 1—and 3-yrs using Kaplan-Meier, Cox proportional hazards, and concordance index. Results: At the first outpatient visit, 15% of patients were stratified as low-risk, 27% as intermediate, and 57% as high-risk. Cumulative 1-year survival rates were 100%, 94%, and 91% for low, intermediate, and high-risk strata, respectively. Cumulative 3-year survival rates were 96%, 89%, and 70% for low, intermediate, and high-risk strata, respectively. We found no difference in outcomes at 1 yr between risk groups. High-risk patients had a significantly higher risk of death at 3 years using REVEAL 2.0 (HR 5.32, p<0.001). However, REVEAL 2.0 accurately discriminated high-risk patients; the Cox proportional hazard ratio was not statistically different between patients classified as intermediate-risk compared to low-risk. Conclusion: REVEAL 2.0 accurately predicted 3-year survival in PH-LHD patients with high-risk features. However, the survival rates in patients classified as intermediate-risk were not significant, suggesting inaccurate classification for this group of patients.

Committee: Patrick Ryan Ph.D. (Committee Chair); Roman Jandarov Ph.D. (Committee Member); Jean Elwing (Committee Member); Jennifer Cook M.D. (Committee Member); Jose Gomez Arroyo M.D. Ph (Committee Member) Subjects: Surgery

PHD, Kent State University, 2005, College of Nursing

Patients with heart failure (HF) are frequently hospitalized due to excessive sodium intake. A behavior promotion model, The Common Sense Model of Illness Representation, was used to determine predictors of self-efficacy for low sodium diet behaviors (Diet SE). When this model was used in non-HF illnesses, the level of threat imposed by implicit illness representation (knowledge about the meaning of an illness [illness beliefs] and symptoms of illness severity [objective cues]) prompted coping through self care behaviors. In addition to the direct threat imposed by an implicit representation, the emotional response to the representation prompted coping. Hypotheses: In patients with HF, (1) accuracy of HF beliefs strengthens Diet SE; (2) greater number of objective HF cues strengthens Diet SE; (3) accuracy of HF beliefs strengthens Diet SE when HF is asymptomatic or mild; (4) depression lessens Diet SE; (5) a combination of HF beliefs, objective HF cues, and depression together predict Diet SE; and (6) when controlling for prespecified control variables, the relationships in hypothesis 5 hold. In 219 patients, more were Caucasian, elderly, married, educated, and non-depressed. Overall, patients had inaccurate HF beliefs and mild objective cues of HF severity. Accurate HF beliefs (all patients and those with mild HF) and number of objective cues did not predict Diet SE (Hypothesis [Ho] 1, 2, and 3). Higher depression predicted less strength in resisting relapse and total Diet SE (Ho 4). When combining predictor variables (Ho 5), the model predicted resisting relapse for Diet SE, but not reducing salt, behavioral skills, or total Diet SE. Age, someone to confide in, and diabetes were associated with Diet SE. After adjusting for these variables, the original combination model relationship with resisting relapse for Diet SE was lost due to the effect of someone to confide in but retained when age and diabetes were entered (Ho 6). Since HF beliefs and cues of severity did (open full item for complete abstract)

Committee: Diana Biordi (Advisor) Subjects: Health Sciences, Nursing

PhD, University of Cincinnati, 2003, Nursing : Adult Health Nursing

The purpose of this study was to determine the ability of selected clinical variables to predict functional capacity measured by maximum oxygen consumption (VO2max) in older women with diastolic heart failure. The clinical predictor variables of interest in this study are the Six-Minute Walk test (6-MW), Body Mass Index (BMI), body weight (WT), E-wave velocity, and E/A wave ratio. The researcher developed a formula that will help health care providers to predict the VO2max for older women with diastolic heart failure. This formula can be useful for clinicians to use as a diagnostic tool and determine prognosis. A descriptive research design using secondary data analysis was selected to address the research questions. The sample for this study consisted of 12 women (mean age= 63.3years, sd = ± 5.4) with diastolic heart failure who completed the VO2 test, the six-minute-walk test (6-MW test), and the Doppler echocardiogram. All of the 12 women from the original study were included in the secondary data analysis. All subjects were considered overweight or obese (mean BMI=35.8 kg/cm2, sd= ± 6.7; fat %= 44.4%, ± 4.5). Linear regression analysis was used to determine which variables provided the best prediction of the dependent variable (VO2 max). The F test was performed to test significance of each model. The overall level of significance was set at the .05 level. Results from the regression analysis were that only the total distance walked during the 6-MW test was found to be a significant and strong predictor, accounting for 60% of the variance in VO2max for older women with diastolic heart failure (R2 = .6, F(1,10) = 14.75, p = .003). The regression equation obtained from the analysis was [Predicted VO2max = 4.7 + .01*(6-MW distance walked)]. Neither BMI or BW nor E/A ratio or E-wave velocity were significant predictors in this sample. This finding supports the ability of the 6-MW test as an alternative screening and diagnostic tool in the clinical settings.

Committee: Dr. Linda Baas (Advisor) Subjects:

Doctor of Philosophy, Case Western Reserve University, 2008, Nursing

Heart failure is the leading cardiovascular disorder in terms of increasing incidence and prevalence in the United States. Based on the Framingham Heart Study, the American Heart Association has estimated that more than 5,200,000 American currently have congestive heart failure. Heart failure is typically associated with marked functional limitation and compromised quality of life (QOL) for the affected individuals and their families. Heart failure is also coupled with clinically relevant psychological impairments such as depression, anxiety, and anger. There were strong relationships among depressive symptoms and various aspects of general and disease specific quality of life. Level of depressive symptoms negatively affected and was predictive of quality of life aspects, although the predictive capability of depressive symptoms did not hold for some aspects of quality of life while controlling for age, gender, EF, BMI, NYHA and number of co-morbidities. Vitamin supplement usage was widely consumed with medical or no medical warrants in this sample of ambulatory heart failure population. Findings from the present study revealed that there was significant positive relationship between NYHA functional class and heart failure-specific quality of life, denoting that those study participants with worse cardiac function also had lower quality of life as a result of heart failure. Furthermore, there were statistically significant relationships among the number of co-morbid conditions the study participants had and the level of perceived quality of life. These findings indicate that the more co-morbid conditions the study patients had, the poorer their general quality of life and their heart failure specific quality of life. However, co-morbidity was not significantly related to vitality, social functioning, and general health. There was a significant relationship between depressive symptoms and heart failure specific quality of life suggesting that study participants with (open full item for complete abstract)

Committee: Joyce Fitzpatrick Joyce (Committee Chair); May Wykle (Other); Mary Quinn Griffin (Other); Jeffrey Albert (Other) Subjects: Health

Master of Arts, The Ohio State University, 2007, Graduate School

Committee: Not Provided (Other) Subjects:

PhD, University of Cincinnati, 2024, Medicine: Molecular, Cellular and Biochemical Pharmacology

The MYBPC3 gene, encoding cardiac myosin protein-c (cMyBP-C), is among the most frequently mutated genes associated with hypertrophic cardiomyopathy (HCM). However, the precise molecular mechanisms underlying how these mutations contribute to the development and progression of HCM remain poorly understood. Consequently, there remains a crucial need for advancing in vitro studies to elucidate these mechanisms and their role in HCM pathogenesis. Accordingly, my PhD dissertation project aimed to investigate the impact and molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in MYBPC3 by using isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs). Successfully generated hCOs were characterized using confocal and electron microscopic analyses, which confirmed the presence of highly organized sarcomeres and the expression of sarcomeric proteins. Functional measurements revealed hypercontractility with increased contraction and relaxation velocity along with faster calcium extrusion in D389V hCOs compared to wild type (WT) hCOs. Protein profiling further confirmed similar expression levels of cMyBP-C with increased phosphorylation in D389V hCOs. Spatial mapping was utilized to identify various cell types and gene expression profiles within the hCOs, revealing the presence of endothelial cells, fibroblasts, macrophages, immune cells, and cardiomyocytes. In vitro, experiments demonstrated reduced binding between cMyBP-C and the Myosin S2 region in the presence of the D389V mutation using recombinant C0-C2 peptides of cMyBP-C. Additionally, cMyBP-C with D389V (MYBPC3D389V) exhibited higher velocity in vitro motility assays compared to their WT counterparts. Due to hyperfunctional sarcomeres, D389V hCOs exhibited heightened oxidative stress and reduced mitochondrial membrane potential. Overall, the present dissertation work showcases the feasibility of assessing both the functional and m (open full item for complete abstract)

Committee: Sakthivel Sadayappan Ph.D. (Committee Chair); Richard Becker (Committee Member); Yi-Gang Wang M.D. (Committee Member); Evangelia Kranias Ph.D. (Committee Member); Jo El Schultz Ph.D. (Committee Member) Subjects: Cellular Biology

Doctor of Philosophy, The Ohio State University, 2024, Molecular, Cellular and Developmental Biology

Heart failure (HF) is one of the leading causes of morbidity and mortality globally. A growing body of evidence has indicated the 5-year mortality rates are about ~50% after initial HF diagnosis. Electrolyte imbalances have been implicated in predicting the outcome of HF patients, where lower serum sodium levels (hyponatremia; serum sodium <135mEq) have been strongly associated with increased mortality in HF. Hence, serum sodium levels have been a well-established adverse prognostic marker for patients with chronic HF. Recent evidence has suggested that lower serum chloride (hypochloremia, <97mEq) is associated with increased mortality risk in patients with chronic HF independent of serum sodium levels. Even though hypochloremia is associated with increased mortality in HF patients, the exact role of chloride (Cl ) homeostasis in cardiac function and how hypochloremia contributes to cardiac injury is unknown. Hence, our study focuses on understanding the mechanism of hyperchloremia-mediated ischemia-reperfusion (IR) injury and the role of Cl- channel in mediating hypochloremia effects. In the first part of this dissertation, we showed that hypochloremia increases mortality in left ventricular assist device (LVAD) placement and acute decompensated HF (ADHF) patients. This increase in mortality was associated with aggravated myocardial infarction post IR injury from our ex vivo studies with isolated rat hearts. In cardiac physiology, hypochloremia increases the beating of hiPSC-CM, which is attributed to increased intracellular calcium (Ca2+) cycling. Since hypochloremia affects the Cl- homeostasis, the mitochondrial functions: membrane potential, and reactive oxygen species production are affected post IR injury. In the second part of this thesis, we have explored the involvement of Cl- channel downstream of hypochloremia on intracellular Ca2+ cycling. Two Cl- channel inhibitors, 4,4'-Diisothiocyanato-2,2'-stilbenedisulfonic acid disodium salt (DIDS), non-specific pl (open full item for complete abstract)

Committee: Harpreet Singh (Advisor); Sandor Gyorke (Committee Chair); Mahmood Khan (Committee Member); Nuo Sun (Committee Member) Subjects: Biochemistry; Biology; Biophysics; Cellular Biology; Molecular Biology

Doctor of Business Administration (D.B.A.), Franklin University, 2024, Business Administration

This qualitative descriptive study explored how healthcare administrators (Pulmonary, Cardiology, or both) describe the influence of Palliative Care on savings for hospitals in the United States. Palliative Care is a supportive service that collaborates with specialists, Primary Care, patients, and families to provide quality care for those with chronic and serious illnesses. Palliative Care is a holistic service that meets physical, social, psychological, and spiritual needs. Patients with congestive heart failure and chronic obstructive lung disease tend to overutilize healthcare services such as the emergency room, admissions, readmissions, and intensive care unit stays. Palliative Care savings are not easily demonstrated on a revenue report but spread across the healthcare system. Hospital leadership may not provide resources for services with a perceived decrease in return on investment. Systems Theory is the central concept used for this study. Systems Theory is how the sum of individual teams or people work together to benefit the patient and, therefore, savings to the hospital. The study's question inquired about the healthcare administrator's experience with Palliative Care and associated hospital savings. The study collected 17 anonymous online surveys utilizing Microsoft Forms from healthcare administrators in the United States. The term healthcare administrators included healthcare administrators, directors, medical directors and managers working in Pulmonology, Cardiology, or both. This researcher invited participants through a recruitment flyer on the investigator's personal Facebook and LinkedIn pages, Facebook and LinkedIn group pages, and Reddit. An invitation was also sent to LinkedIn Connections and Facebook Friends by direct message for those who may be eligible for the study. Participants participated anonymously, and the researcher asked them to refrain from responding over direct messages. The researcher analyzed data using ATLAS (open full item for complete abstract)

Committee: Beverly Smith (Committee Chair); Gary Stroud (Committee Member); Steven Tincher (Committee Member) Subjects: Business Administration; Health Care; Health Care Management; Medicine; Nursing; Public Health

DNP, Walsh University, 2024, Nursing

Depression is a prevalent concomitant illness in adults with heart failure (HF) that is frequently misdiagnosed and untreated. The American Heart Association's (AHA) guidelines recommend screening with the PHQ-2 initially, followed by the PHQ-9 if the PHQ-2 is positive. Therefore, the purpose of this DNP project was to increase depression screening among patients with HF in homecare settings by implementing an evidence-based screening method. A non-experimental pre-/post-test comparative design was implemented to compare nurse practitioners' (NP) knowledge of depression in HF pre/post education. Knowledge of depression in HF increased following an educational session with a pre-mean knowledge score of 70.4% and a post-mean knowledge score of 92.9%. Data was also collected to assess the frequency of depression screening and treatment before and after NP education. A retrospective chart review was conducted of 128 patient charts. Prior to NP education, no patients were screened for depression using the PHQ-2 and PHQ-9 tools even though they were available in the electronic health record. One month following NP education, 76% of patients were screened for depression. Patients who screened positive on the PHQ-2 were further screened with the PHQ-9. Antidepressant medication was initiated in three patients, while one continued to be monitored. Project findings revealed that both nurse knowledge and screening of patients for depression increased post education. It is recommended annual NP education of depression in HF patients and ongoing screening in home care settings continue. Early identification and timely treatment of depression can improve outcomes for older adults with HF.

Committee: Cheryl Bradas (Advisor); Shelly Amato-Curan (Committee Chair) Subjects: Nursing

Doctor of Philosophy, The Ohio State University, 2024, Biomedical Sciences

Heart failure is a leading cause of death in the United States and worldwide. Heart failure is defined simply as the inability of the heart to pump a sufficient volume of blood to meet the metabolic needs of the body. This can occur because of impaired ability of the heart to relax and refill with blood (diastolic dysfunction) or because of impaired contractility (systolic dysfunction). Current standards of care for heart failure treat symptoms and can alleviate some symptoms, however, there are currently no approved therapies that directly improve heart function. Therefore, it is necessary to find alternative mechanisms to beneficially increase heart function and improve outcomes for heart failure patients. One key mechanism by which cardiac contraction and relaxation are regulated is by calcium binding to myofilament regulatory proteins. Cardiac contraction is initiated upon increased intracellular calcium. Calcium then binds to the thin filament protein troponin C (TnC), resulting in a conformational change that exposes myosin binding sites on actin allowing myosin cross bridge formation and the sarcomere can shorten. Relaxation is also an active process: following the decrease in intracellular calcium, the thin filament is actively returned to a blocking state, inhibiting actin-myosin interaction. A healthy heart is able to alter this process to increase its function through post-translational modifications. In the classic example of beta-adrenergic signaling, the activation of protein kinase A (PKA) results in the phosphorylation of many proteins within the myocyte including those that affect calcium transients and myosin cycling. Importantly, PKA also phosphorylates the inhibitory subunit of the troponin complex, troponin I (TnI), at serine (S) residues 23 and 24. This phosphorylation has been well characterized to change the responsiveness of the myofilament proteins to calcium, or to decrease calcium sensitivity, therefore accelerating relaxation to incr (open full item for complete abstract)

Committee: Brandon Biesiadecki (Advisor); Sakima Smith (Committee Member); Jill Rafael-Fortney (Committee Member); Mark Ziolo (Committee Member) Subjects: Biomedical Research; Cellular Biology; Physiology

Doctor of Philosophy, The Ohio State University, 2024, Biomedical Sciences

Heart failure (HF) is a complex heterogeneous syndrome characterized by altered left ventricular ejection function and impacts over six million individuals in the United States. Among cancer survivors, cardiovascular mortality due to HF is prevalent.1,2 Despite improvements in the medical and surgical management of HF, mortality rates remain high, with only modest improvements in survival during the past decade. Proper systolic heart function requires coordinated activation and force transmission throughout the myocardium. Cardiomyocytes have developed intricate molecular mechanisms to control both electrical and mechanical functions in response to physiological and pathological stressors. Therefore, active targets for diagnostic and therapeutic approaches for HF are currently centered on pathways that influence both the electrical and structural function of cardiomyocytes. The work described herein explores the mechanisms underlying electrical and structural dysfunction in tyrosine kinase inhibitor (TKI) cardiotoxicity and βII-spectrin (Sptbn1) deficient HF. Genetic or acquired (i.e., drug-induced cardiotoxicity) changes in signaling pathways responsible for electrical and structural homeostasis can lead to the development of lethal arrhythmias and HF. Several chemotherapeutic agents, including TKIs, are associated with arrhythmia and HF in patients with or without preexisting cardiovascular disease. It has been postulated that TKIs may induce HF by causing direct myocardial damage, culminating in reduced cardiac inotropy, lusitropy, and chronotropy. However, the mechanisms by which these phenomena develop or contribute to ventricular arrhythmias and cardiac dysfunction are incomplete. We first describe that pazopanib, a second-generation TKI, alters cardiomyocyte excitability in patients using a retrospective chart review and recapitulated these findings in two mouse models using surface electrograms. Cellular and computational model studies revealed th (open full item for complete abstract)

Committee: Sakima Smith (Advisor); Brandon Biesiadecki (Committee Member); Mark Ziolo (Committee Member); Jill Rafael-Fortney (Committee Member); Thomas Hund (Committee Member) Subjects: Cellular Biology; Molecular Biology; Physiology

Doctor of Philosophy, The Ohio State University, 2024, Biomedical Sciences

Heart disease remains the leading cause of death in the United States with heart failure specifically accounting for 13.4% of all heart disease-related deaths. In 2019, Andersson et al., utilized a multi-omics approach to evaluate participant samples from the Framingham Heart Study and showed that ankyrin-R (AnkR; encoded by ANK1) is associated with diastolic function, left ventricular remodeling and heart failure with preserved ejection fraction. Ankyrins are a family of proteins that link integral membrane proteins with the actin/β-spectrin cytoskeleton. Ankyrins-B/G have been extensively studied and identified within the heart and their dysfunction is associated with cardiac structural and electrical phenotypes. Ankyrin-R, first identified in erythrocytes, has yet to be studied in the context of cardiac function, heart failure or arrhythmias. To study AnkR in the context of the heart we isolated tissues from adult wild-type mice as well as isolated myocytes and cardiac fibroblasts and performed immunoblot and qPCR analysis for ankyrin-R protein and Ank1 mRNA expression. Concurrently, we generated an Ank1-cKO mouse to genetically delete canonical AnkR in cardiomyocytes under the αMHC promoter. We found that isolated cardiomyocytes express only the small AnkR isoform while cardiac fibroblasts express the canonical large AnkR isoform at both the protein and mRNA level. Canonical AnkR is diffusely expressed in the fibroblast membrane, cytoplasm, cytoskeleton, and soluble nuclear fractions. Further, when AnkR is knocked out of cultured fibroblasts we observed a significant decrease in contractility. When we generated an Ank1-ifKO mouse model to selectively delete AnkR in activated fibroblasts, we observed no significant increase to fibrotic deposition after AngII/PE challenge. These results are the first to show canonical AnkR expression specifically within the cardiac fibroblasts and the loss of AnkR, coordinating with Golgi machinery, reduces the amount and changes (open full item for complete abstract)

Committee: Peter Mohler (Advisor); Sara Koenig (Advisor); Mona El Refaey (Committee Member); Thomas Hund (Committee Member); Sakima Smith (Committee Member) Subjects: Biomedical Research; Cellular Biology; Molecular Biology

Master of Sciences (Engineering), Case Western Reserve University, 2023, Biomedical Engineering

Recent studies have highlighted the pathophysiological significance of epicardial adipose tissue (EAT) in the development of heart failure (HF). Using EAT image features (hereafter fat-omics) extracted from low-cost (no-cost at our institution) CT calcium score (CTCS) images, we predicted HF onset. We segmented EAT using a modified version of our deep learning algorithm, DeepFat, edited cases for accuracy, and collected 87 hand-crafted features (fat-omics) including volume, spatial, thickness, and HU values, as elevated HU is thought to be an indicator of inflammation. We included readily available clinical and demographic features (e.g. age, sex, and BMI). We used a dataset of HF-enriched patients (N=1,988, HF: 5.13%) and a Cox model with stepwise feature reduction, trained on 80% and evaluated with 20% held-out testing. High risk features (e.g., mean EAT thickness, EAT mean HU, and smoking) were identified using univariate analyses. Fat-omics, clinical and demographic features predicted HF with C-index/2-year AUC of 72.7/71.8, respectively. For comparison, different models using BMI, EAT volume, pericardial sac volume and a combined set of clinical and demographic features gave training/testing C-index values of 59.7/58.8, 60.0/59.8, 61.0/59.2 and 68.6/67.5, respectively. Additionally, we evaluated the calcification Agatston score, which is used to predict atherosclerosis-related major adverse cardiac events. It yielded training/testing of 62.7/62.9. Fat-omics, clinical and demographic features also gave excellent stratification of patients into low- and high-risk groups using Kaplan-Meier plots with a net reclassification improvement (NRI) of 0.11 (p-value=0.024) as compared to EAT Volume alone. Our results demonstrate that EAT plus simple clinical and demographic features might be used to predicting HF onset.

Committee: David Wilson (Committee Chair); Juhwan Lee (Committee Member); Shuo Li (Committee Member) Subjects: Biomedical Engineering; Health Care Management; Statistics

Doctor of Philosophy, The Ohio State University, 2023, Biomedical Engineering

Heart rate constantly fluctuates from beat-to-beat on a timescale ranging from seconds to hours under physiological conditions, termed heart rate variability (HRV). Clinical studies have shown that reduced HRV correlates with an increased risk for cardiac arrhythmias in various diseases, like chronic heart failure (CHF). HRV also influences the formation of pro-arrhythmic alternans, a beat-to-beat alternation in intracellular calcium (Ca) levels or the action potential duration (APD), which can form at different spatial scales. In this thesis, I investigate the impact of fluctuations in heart rate on alternans formation and arrhythmic propensity in various physiological and pathological conditions. I show that high HRV has anti-arrhythmic effects, such as mitigating the effects of subcellular Ca alternans formation. I also generate long-term, patient-specific simulations using patient RR sequences and a normal sinus rhythm and CHF model and demonstrate that both specific changes in heart rate and CHF-associated remodeling influence APD alternans formation. Finally, I examine the relationship between changes in RR sequence statistical properties and arrhythmia formation in Dravet Syndrome, a type of genetic epilepsy. My results suggest that the time course of response to epinephrine/caffeine treatment is a potential biomarker for arrhythmia-related Sudden Unexpected Death in Epilepsy in Dravet Syndrome.

Committee: Seth Weinberg (Advisor); Rengasayee Veeraraghavan (Committee Member); Thomas Hund (Committee Member) Subjects: Biomedical Engineering; Medicine; Physiology

Doctor of Philosophy, The Ohio State University, 2023, Biomedical Engineering

Cardiovascular disease is a leading cause of death and is growing in prevalence, afflicting almost 50% of American adults and contributing to about one fifth of yearly deaths in the United States alone. The increasing incidence is driven largely by the prevalence of chronic diseases like obesity, atrial fibrillation, and heart failure, each of which are associated with additional risk factors, including development of cardiac arrhythmias. Although previous studies have identified a range of molecular players involved in disease pathogenesis via structural remodeling, ion channel dysfunction, and acquired Ca2+-handling defects, many of the current therapies for treatment of chronic heart disease are limited by cost, accessibility, efficacy, and detrimental side-effects. Recent work has identified putative roles for the TWIK-related K+ channel 1 (TREK1) in modulating cardiac excitability and pacemaking in normal physiology and disease. Additionally, upregulation of late Na+ current by Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of the cardiac voltage-gated Na+ channel (Nav1.5) has been implicated in atrial fibrillation. However, the involvement of each of these targets in arrhythmogenesis and cardiac remodeling resulting from chronic stress, such as in diet-induced obesity or heart failure, is largely understudied. In the present studies, it was hypothesized that chronic stress conditions promote dysfunction of Na+ and K+ channels to promote electroanatomical remodeling via a combination of disrupted Ca2+ homeostasis and non-canonical signaling pathways. To test this hypothesis, a combination of experimental techniques were employed, including genetic mouse models, bioimaging, molecular biology, metabolic testing, and diverse electrophysiological techniques. These studies demonstrate that inhibition of CaMKII-dependent upregulation of the Nav1.5 late Na+ current reduces atrial arrhythmia susceptibility, inhibits fibrotic remodeling, and impro (open full item for complete abstract)

Committee: Thomas Hund (Advisor); Przemyslaw Radwanski (Committee Member); Sakima Smith (Committee Member); Isabelle Deschenes (Committee Member) Subjects: Biomedical Engineering; Biomedical Research

Doctor of Philosophy, The Ohio State University, 2023, Biomedical Engineering

Quantitative colocalization analysis is a standard method in the life sciences used for evaluating the global spatial proximity of labeled biomolecules captured by fluorescence microscopy images. It is typically performed by characterizing the pixel-wise signal overlap or intensity correlation between spectral channels. However, this approach is critically flawed due to its focus on individual pixels which limits assessment to a single spatial scale constrained by the pixel's size, thus making the analysis dependent on the achieved optical resolution and ignorant of the spatial information presented by non-overlapping signals. In this dissertation, I present an improved method for quantifying biomolecule spatial proximity using a novel application of point process analysis adapted for discrete image data, and subsequently utilize it to address two novel cardiac conundrums. The tool, called Spatial Pattern Analysis using Closest Events (SPACE), leverages the distances between signal-positive pixels to statistically characterize the spatial relationship between labeled biomolecules from fluorescence microscopy images. In chapter two, SPACE's underlying theory and its adaption for discrete image-based data is described. Additionally, I characterize its sensitivity to segmentation parameters, image resolution, and signal sample size, and demonstrate its advantages over standard colocalization methods. With this tool, I hope to provide microscopists an improved method to robustly characterize spatial relationships independent of imaging modality or achieved resolution. In chapter three, SPACE is used to elucidate a novel, microtubule-based system for the distributed synthesis of membrane proteins in cardiomyocytes. Canonically, these cells are thought to produce membrane proteins in the peri-nuclear rough endoplasmic reticulum, then leverage the secretory-protein-trafficking pathway to transport nascent proteins to their sites of membrane insertion. By labeling car (open full item for complete abstract)

Committee: Rengasayee Veeraraghavan (Advisor); Przemysław Radwański (Committee Member); Peter Craigmile (Committee Member); Seth Weinberg (Committee Member) Subjects: Biology; Biomedical Engineering; Biomedical Research; Biophysics; Biostatistics; Cellular Biology; Engineering; Scientific Imaging; Statistics

DNP, Otterbein University, 2023, Nursing

Congestive Heart failure patients have the highest readmission rate within 30 days of discharge placing a significant burden on healthcare costs and quality of life for the patient and families. Community Emergency Medical Services are the first to respond to moderate to severe exacerbation of Congestive Heart Failure (CHF) patients' calls. Involving Emergency Medical Services in a preventive approach rather than just responding to exacerbation calls has proven to be effective in pilot studies to prevent heart failure readmissions. The purpose of this Scholarly project was to develop evidence-based recommendations for community Emergency Medical Services' involvement in the management of congestive heart failure patients to reduce the readmission rate. The John Hopkins Evidence-Based Practice Model (JHEBP) was utilized to fulfill the project aim. Utilizing the model following steps and goals were established 1) Review and analyze the evidence on the current practice of community Emergency Medical Services' involvement and treatment of congestive heart failure patients. 2) Develop evidence-based recommendations to reduce CHF readmission in the prehospital setting, and 3) Develop a plan to monitor the effectiveness of recommendations. This project was significant because it helped to create evidence-based recommendations for the reduction of CHF readmission in prehospital settings. Although the recommendations could not be implemented due to the limited time frame of the academic timeline, this study can be considered as a starting point for further implementation and study purposes. Keywords: Congestive heart failure, emergency medical services, Emergency Medical Services, prehospital, community, protocol, guideline procedures.

Committee: Dr. Kirk Hummer (Advisor); Dr. Chai Sribanditmongkol (Committee Member); Dr. Joy Shoemaker (Other) Subjects: Nursing

Master of Arts, The Ohio State University, 2023, Educational Studies

There is a need for additional training in advanced heart failure for adult congenital heart disease (ACHD) cardiology fellows given the growing population of ACHD patients with advanced heart failure. The goal of this study was to evaluate if a competency-based curriculum in advanced heart failure for the adult cardiology-trained ACHD fellow could be developed utilizing both pediatric and adult heart failure training experiences and not prolong time in training. Utilizing a theoretical framework of experiential learning and critical reflection, the competency- based curriculum was designed first by evaluating the overlap in Milestones from the Accreditation Council for Graduate Medical Education for both ACHD and adult advanced heart failure and transplant cardiology (AHFTC). Learning objectives were then developed based on core competencies from the AHFTC training curriculum, and adapted for the ACHD fellow by removing post-transplant care and integrating learning objectives from the Pediatric Heart Failure Core Competency Curriculum from the International Society for Heart and Lung Transplantation. Experts in ACHD and pediatric and adult heart failure developed curricular experiences to meet the learning objectives, including adult and pediatric clinical rotations, conferences, synchronous and asynchronous learning resources, with a focus on the longitudinal care of identified ACHD patients with advanced heart failure. Training time may vary based on the prior experience of the fellow, though it utilizes elective time within the ACHD fellowship such that training is not prolonged. In conclusion, a competency-based curriculum in heart failure for the adult cardiology-trained ACHD fellow is feasible and has been successful with 1 fellow thus far, with pre-defined competencies which align with the role the ACHD fellow will have in the next stage of their career.

Committee: Sakima Smith (Committee Member); David Stein (Advisor) Subjects: Education; Health Education; Medicine

Doctor of Philosophy, The Ohio State University, 2023, Biomedical Sciences

Although impressive progress has been made to reduce the burden of heart disease, the illness remains the leading cause of death in the world. Notably, many types of persistent heart injury can cause pathological remodeling of the heart and progression to heart failure. The overall goal of my dissertation is to dissect novel molecular pathways responsible for such transition, since targeting them therapeutically presents an exciting opportunity to slow down heart remodeling and improve survival. While transcriptional regulators of progression to heart failure have been studied extensively, the importance of post-transcriptional regulation, such as chemical modification of messenger RNA, has been overlooked. Recent critical studies from our group and others demonstrated that methylation of mRNA in position N6 of adenosines (m6A) was essential for the heart's ability to adapt to stress, but the downstream regulators of this mechanism have remained elusive. Moreover, the field lacked a clear understanding of which cardiac m6A targets are most relevant and how they are regulated. After methylation, m6A-modified mRNAs are recognized by specific mRNA-binding proteins belonging to the YTH domain family (YTHDF), of which YTHDF1 and YTHDF2 are two key members expressed in the heart. In my work, I examine their specific contributions to the regulation of cardiomyocyte biology and their mechanistic effects on the distinct cardiac mRNA transcripts. First, I investigate the role of YTH N6-Methyladenosine RNA Binding Protein 2 (YTHDF2) in the heart using an inducible loss-of-function mouse model. I find that YTHDF2 protein is elevated in the failing mouse hearts and is essential for maintenance of cardiac homeostasis. Loss of YTHDF2 drives cardiac hypertrophy, fibrosis, and dysfunction in mice in the absence of any apparent stress. Furthermore, I detect that the proteome of YTHDF2-null cardiomyocytes is significantly remodeled, corroborating the importance of YTHDF2 in the re (open full item for complete abstract)

Committee: Federica Accornero, PhD (Advisor); Michael Kearse, PhD (Committee Member); Sakima Smith, MD, MPH (Committee Member); Kedryn Baskin, PhD (Committee Member) Subjects: Biomedical Research; Cellular Biology; Molecular Biology; Molecules; Physiology