MS, University of Cincinnati, 2024, Medicine: Genetic Counseling

Genetic counseling services are an important component of care for pediatric cardiac patients. The financial costs and benefits of this care have yet to be defined in the literature. Downstream revenue analysis can be used to assess the economic impact of genetic counselors (GCs) at their institution beyond the initial point of patient contact. Previous literature has reported downstream revenue generated by oncology GCs, but there is no known published downstream revenue data from a cardiac GC setting. This study measured the downstream revenue generated at a single institution following a cardiac GC appointment. A chart review identified patients seen by a cardiac GC between 2018 and 2022. The study population includes patients and their family members age 18 and under who had not previously seen a cardiologist at our institution and were affected with or at-risk for long QT syndrome, hypertrophic cardiomyopathy, dilated cardiomyopathy, or familial thoracic aortic aneurysm. We calculated the reimbursement for all cardiology services received for one year following the proband's initial GC appointment. We recorded the frequency of common cardiac services. The billing cohort included 61 families and 121 participants who were primarily at-risk relatives of affected individuals and presented for screening rather than invasive procedures or inpatient stays. The total downstream revenue was $247,592.27 over 4.5 years, with a median of $1,819.50 per patient per year (IQR $0, $3,761.33) and $3,341.76 per family per year (IQR $46.01, $7,318.09). Revenue was similar among individuals who had undergone genetic testing and those who had not. Dilated cardiomyopathy patients generated the highest revenue ($137,936.93 for 60 participants), and long QT syndrome patients generated the lowest revenue ($5,747.35 for 15 participants). Among participants, 72 (59.5%) had subsequent cardiology services. Most frequently, a patient who presented for subsequent care had an (open full item for complete abstract)

Committee: Carrie Atzinger M.S. C. (Committee Chair); Erin Miller M.S. L. (Committee Member); Amy Shikany MS (Committee Member); Christopher Statile (Committee Member); Sara Knapke M.S. (Committee Member); Lisa Martin Ph.D. (Committee Member); Jeffrey Anderson (Committee Member) Subjects: Genetics

Master of Science, The Ohio State University, 2019, Genetic Counseling

With the recent advent of next generation sequencing, the genetic evaluation of patients with skeletal myopathies and cardiomyopathies now frequently includes sequencing of many genes, including those whose large size previously precluded testing, such as TTN. While this technology has increased the number of cases which receive a genetic diagnosis, the clinical implications of a specific genetic finding are not always well-established. Genetic variants of uncertain significance present challenges with respect to clinical interpretation and patient care. Emerging data suggests that many pathogenic variants may be associated with a broader range of phenotypes than previously recognized. Variants in TTN have proven particularly challenging, given their frequency in the general population and that, historically, only portions of the gene were sequenced. Pathogenic variants in TTN are currently known to cause dilated cardiomyopathy (DCM) and several skeletal myopathies without cardiac involvement. Dominant truncating variants in the A-band are the leading genetic cause of DCM; affected individuals are not known to have skeletal muscle involvement. Known skeletal myopathies associated with TTN include: tardive tibial muscular dystrophy (caused by dominant M-line variants), limb-girdle muscular dystrophy type 2J (caused by a homozygous-M line deletion), hereditary myopathy with early respiratory failure (caused by dominant missense variants in exon 344), and centronuclear myopathy (caused by recessive truncating or in-frame deletions/duplications). In addition, recessive truncating TTN variants have also been reported to cause several severe childhood-onset phenotypes presenting with both skeletal and cardiac muscle disease, including early-onset myopathy with fatal cardiomyopathy. We hypothesize that heterozygous truncating variants in the A-band may also cause a distinct, novel phenotype including both cardiac and skeletal muscle disease. The goal of th (open full item for complete abstract)

Committee: Jennifer Roggenbuck (Advisor); Ana Morales (Committee Member); Guy Brock (Committee Member) Subjects: Genetics; Medicine

Master of Science in Biomedical Sciences (MSBS), University of Toledo, 2020, Biomedical Sciences (Bioinformatics and Proteomics/Genomics)

Dilated cardiomyopathy (DCM) belongs to the heterogeneous group of heart muscle disorders called cardiomyopathies, characterize by left ventricular dilatation and reduce myocardial muscle contractility that leads to a reduced ejection fraction of the heart. There are several causes of DCM; genetic, toxic, metabolic, endocrine, infiltrative, and idiopathic disorders. Forty causative genes encoding for a variety of proteins have been identified up to date. The objective of this study is to identify potential biomarkers related to the disease process of DCM. Microarray and RNA-Seq profiles of cardiac tissue were used to identify differentially expressed genes (DEGs). Four Microarray datasets (GSE 3585, GSE3586, GSE9800, and GSE42955), and three RNA-Seq datasets were selected (GSE55296, GSE65466, and GSE71613) from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was used to explore the hub genes involved in the disease process of DCM. A total of 51 modules for microarray datasets and 15 modules for RNA-Seq datasets were identified using correlation network analysis. Four common statistically- significant genes were identified among these modules, including AP3M2, ECM2, ERBB2, and ZNF83. AP3M2 gene, which involves protein trafficking to lysosomes and specialized organelles, ECM2 gene, which affects in extracellular matrix protein function, ERBB2 gene, which involves in Erb-B2 Receptor Tyrosine Kinase 2 signaling pathway, and ZNF83 gene which involves in transcriptional regulation in the cell. A total of 9 hub genes that were differentially over-expressed significantly in cardiac tissue from RNA-Seq datasets, including EIF4GA which is related to viral myocarditis, HACD1, MYOM3, PTPN4, and NRBP1 are associated with muscular disorders, CELSR which play an essential role for planar cell polarity, SLC27A6 which is transporter involve in LCFA uptake process, SCMH1 involves in negative regulation of gene expression, and DC (open full item for complete abstract)

Committee: Sadik Khuder (Committee Chair); Robert Blumenthal (Committee Member); Jiang Tian (Committee Member) Subjects: Bioinformatics; Biomedical Research; Genetics

Master of Science (MS), Wright State University, 2019, Anatomy

Dilated cardiomyopathy (DCM) is one the most common forms of heart failure, with the majority of cases being idiopathic. Dr. Bennett's laboratory previously showed that deletion of the Mgat1 gene in cardiomyocytes only (Mgat1KO) is sufficient to cause DCM leading to heart failure and early death. The Mgat1 gene product, GlcNAcT1, is responsible for initiating the formation of hybrid/complex N-glycosylation. These data suggest a link between abnormal glycosylation and heart disease; however, there is a mystery of how the specific changes in glycosylation contribute to heart disease etiology and progression. The proper function and gating of voltage-gated Na+ channels (Nav) and voltage-gated K+ channels (Kv) are vital to the initiation, shape, and conduction of the cardiomyocyte action potential (AP); thus, abnormal channel activity contributes to arrhythmias and other heart diseases. Other labs as well as our own, have shown that modest reductions in channel glycosylation can alter gating of Nav and Kv through electrostatic mechanisms with no change in channel expression levels. Thus, here and in a recent publication by Ednie, Parrish, Sonner, and Bennett entitled, “Reduced Hybrid/Complex N-glycosylation Disrupts Cardiac Electrical Signaling and Calcium Handling in a Model of Dilated Cardiomyopathy“, we showed that cardiomyocyte-specific deletion of Mgat1 that leads to reduced hybrid/complex protein N-glycosylation modulates Nav and Kv activity through direct and indirect mechanisms. Here, we show that Mgat1KO Nav expression was not different between Mgat1KO and control ventricular myocytes; however, there was a reduction in Mgat1KO Nav molecular weight, suggesting that Nav are direct targets of GlcNAcT1 similar to Cav 21. We found that Kv4.2 and Kv1.5 expression levels are significantly lower in the older Mgat1KO ventricular myocyte compared to controls, consistent with an indirect, but disease-related decrease in Kv expression and, as a result, K+ current. (open full item for complete abstract)

Committee: Eric Bennett Ph.D. (Advisor); Mark Rich M.D., Ph.D. (Committee Member); Kathrin Engisch Ph.D. (Committee Member); Nick Ritucci Ph.D. (Other) Subjects: Anatomy and Physiology; Biochemistry; Cellular Biology; Molecular Biology

Master of Science, The Ohio State University, 2016, Medical Science

Purpose Recent advances have expanded our knowledge of the genetic etiology of dilated cardiomyopathy (DCM). With these advances, recommendations for cardiovascular screening and genetic testing of patients and families with DCM have been published, including involvement of genetic counselors in the healthcare team caring for these individuals. However, little research is available describing the psychosocial concerns experienced by DCM patients and their families. This study thus sought to identify recurring psychosocial concerns of DCM patients and their families, as well as identify correlations between demographic and health history information with the expression of these concerns. Methods Qualitative analysis, using components of grounded theory and constant comparison, was performed examining follow-up correspondence data recorded from DCM Research Project participants. Thematic categories were created, refined, and validated by a second independent reviewer. After thematic analysis was completed, selected participants representing key thematic findings were contacted for follow-up telephone interviews to provide deeper insight into the concerns expressed. Statistical correlations were performed using phi coefficients and point biserial analyses comparing the emergent themes with demographic information as well as clinical data available for participants. Results From 1638 eligible participants, 430 data points were coded from the correspondence of 239 individuals from 158 kindreds. A total of 152(63.4%) were female and 87 (36.6%) were male. Most participants (89.5%) were non-Hispanic Caucasian. Eight thematic categories were identified: Concern for children/relatives (n=115, 26.7%); Emotional adjustment (n=61, 14.2%); Communication (n=56, 13.0%); Research (n=51, 11.9%); Insurance (n=51, 11.9%); Genetics (n=37, 8.6%); Physician issues (n=34, 8.6%); Disease/Medications/Treatment (n=25, 5.8%). From 19 participants selected for follow-up interviews, (open full item for complete abstract)

Committee: Ana Morales (Advisor) Subjects: Counseling Education; Genetics; Health Care

PhD, University of Cincinnati, 2015, Medicine: Molecular, Cellular and Biochemical Pharmacology

In this dissertation, we identified two novel human mutations in the major Ca2+-handling proteins, PLN and Hsp20, in patients with DCM. Specifically, exome sequencing identified a C73T substitution in the coding region of PLN in a family with DCM. This C73T substitution results in the change of arginine at position 25 into cysteine, which is called R25C. It was found that the 4 heterozygous family members had implantable cardiac defibrillators, and 3 developed prominent ventricular arrhythmias. The second mutation in Hsp20 is S10F, which was identified in DCM patients with a frequency of 2.8%, while there were no normal subjects carrying the S10F-Hsp20. To determine if there are correlative or causative relationships between the two mutations and the observed clinical phenotypes in human carriers, the effects of R25C and S10F mutations on cardiac function were investigated by utilizing adenoviral infected rat cardiomyocytes and transgenic mouse model respectively. First of all, this dissertation reveals that overexpression of R25C-PLN in adult rat cardiomyocytes significantly suppressed the Ca2+ affinity of SERCA2a, causing decreased SR Ca2+ content, Ca2+ transients and impaired contractile function, compared to WT-PLN. These inhibitory effects were associated with enhanced interaction of R25C-PLN with SERCA2a, which was prevented by PKA phosphorylation. However, R25C-PLN also elicited increases in the frequency of Ca2+ sparks and waves as well as stress-induced aftercontractions. This was accompanied by increased CaMKII activity and hyper-phosphorylation of RyR2 at serine 2814. Regarding the role of S10F-Hsp20 in cardiac function, in vitro studies in infected cardiomyocytes showed that the inotropic effects of Hsp20 were negated by S10F. Furthermore, S10F significantly abrogated the protective effects of WT-Hsp20 upon prolonged isoproterenol-stimulation. To investigate the in vivo impact of S10F-Hsp20, transgenic mice with cardiac-speci?c overexpression of this (open full item for complete abstract)

Committee: Guochang Fan Ph.D. (Committee Chair); Evangelia Kranias Ph.D. (Committee Chair); Walter Jones Ph.D. (Committee Member); Jo El Schultz Ph.D. (Committee Member); David Wieczorek Ph.D. (Committee Member) Subjects: Health Sciences

PhD, University of Cincinnati, 2006, Medicine : Molecular, Cellular and Biochemical Pharmacology

Cardiac hypertrophy and dilatation are mediated by neuro-endocrine factors, internal stretch and stress sensitive signaling pathways, which in turn transduce alterations in cardiac gene expression through specific transcription factors. This dissertation will, in the first section, provide direct evidence for transcription factor myocyte enhancer factor 2 (MEF2) in the regulation of cardiac dilation and fibrosis through reprogramming cardiac gene expression; in the second section, introduce a novel secreted factor growth differentiation factor 15 (GDF15) as a cardiac anti-hypertrophic and protective factor. The MEF2 family of transcription factors have been indirectly implicated as a downstream mediator of hypertrophic signaling pathways. In this dissertation, we demonstrate directly that MEF2 induce dilated cardiomyopathy and the lengthening of myocytes without a primary induction of cardiac hypertrophy. Cardiac-specific overexpression of MEF2A or MEF2C showed spontaneous cardiomyopathy, which was not altered by activated calcineurin, or developed more fulminant disease following pressure overload. In cultured cardiomyocytes, MEF2A and MEF2C overexpression induced sarcomeric disorganization and focal elongation. Mechanistically, MEF2A and MEF2C programmed similar alteration in gene expression that included extracellular matrix remodeling, ion handling, and metabolic genes. Indeed, cultured cardiomyocytes overexpressing MEF2A, or adult myocytes from MEF2A transgenic hearts, showed reduced transient outward currents, suggesting a proximal mechanism underlying MEF2-dependent cardiomyopathy. During the analysis of gene reprogramming by MEF2, we noted dramatic induction of GDF15. GDF15 is induced by conditions that promote hypertrophy and dilation. Transgenic mice with cardiac-specific overexpression of GDF15 were normal, but were partially resistant to induced hypertrophy. GDF15 antagonized induced hypertrophy in cultured cardiomyocyte. Transient expression of GDF15 by (open full item for complete abstract)

Committee: Dr. Jeffery Molkentin (Advisor) Subjects:

Doctor of Philosophy, The Ohio State University, 2009, Nursing

Background: Becker muscular dystrophy is caused by dystrophin gene mutations resulting in skeletal and cardiac muscle degeneration. When cardiac manifestations are more prominent than, or disproportionate to skeletal muscle involvement, the disorder is diagnosed as X-linked dilated cardiomyopathy. Dystrophin mutations predictive of dilated cardiomyopathy have been suggested, but representative examples from the literature are insufficient in number to establish with certainty. Defining the cardiac presentations of specific mutations is crucial for risk classification, early detection and treatment of dilated cardiomyopathy to prolong survival. From the patient's perspective, knowing how his individual genotype affects cardiac outcome may be beneficial for health management and life planning. Purpose: To determine age of dilated cardiomyopathy manifestation in relation to dystrophin gene mutation patterns and its resulting dystrophin protein modifications in Becker muscular dystrophy and X-linked dilated cardiomyopathy patients. Methods: Becker muscular dystrophy and X-linked dilated cardiomyopathy patients with dystrophin exon (building blocks of a gene) deletion mutations and with cardiac histories were collected from multiple sources. The correlations between dystrophin gene mutation patterns and age of dilated cardiomyopathy manifestation were established. Protein modeling was conducted to evaluate structural consequences caused by dystrophin genetic mutations. Results: Data of 110 patients were included in this study, of which 76 had dilated cardiomyopathy. Exon deletions in the amino-terminal domain (the beginning part of the dystrophin protein) of dystrophin resulted in the earliest mean age of cardiac involvement (22.5 years). Mutations affecting the spectrin repeats in the rod domain preserving Hinge 3 (the central part of the dystrophin protein) lead to the intermediate age of cardiomyopathy onset (29.5 years), followed the latest age of onset (46.5 years) (open full item for complete abstract)

Committee: Donna McCarthy PhD (Advisor); Federica Montanaro PhD (Committee Member); Wendy Blakely PhD (Committee Member) Subjects: Genetics; Health; Molecular Biology; Nursing

Doctor of Philosophy, The Ohio State University, 2002, Veterinary Biosciences

Canine dilated cardiomyopathy (DCM) induced by rapid pacing produces low cardiac output failure, mimicking naturally occurring human DCM. We studied long-range (>6 months) rapid right ventricular pacing to evaluate similarities to end-stage human DCM and determine differences from previously reported canine pacing studies. Samples were obtained from the right and left auricles (RAU, LAU), right and left atria (RA, LA), right and left ventricles (RV, LV), and LV subauricular and subatrial papillary muscles (PM) from 12 pacing and 11 control dogs. Since both beagle and mongrel hounds commonly are used in models of human DCM, we also investigated levels of cardiac myosin heavy chain (MHC) isoforms from 6 beagle and 6 mongrel controls. Distinct differences were observed, compared to previously reported, shorter-range studies, in numbers of apoptotic myocytes, cross-sectional myocyte size, and Bcl-2 protein levels. Myocyte degeneration and mitochondrial degradation were apparently more severe than previous reports. Rod body formation, indicative of severe myocyte degeneration, was observed. In addition, lower numbers of apoptotic myocytes, increased cross-sectional area with apparent wider size distribution and comparable levels of both Bcl-2 and Bcl-xL on western blot were observed in this study, different from previous pacing studies, but similar to end stage human heart failure. Differences in amounts of apoptosis and type II myocyte nuclei were observed based on sampling location, suggesting variation in cellular response to injury. Significant increases in levels of Beta MHC were observed in the RAU, RA, LAU, LA, and RV of pacing dogs compared to control. In addition, significant levels of ventricular light chain 2 (VLC2) were observed in the RA of pacing dogs, suggesting a compensatory switch in response to prolonged elevated RA pressure. Distinct differences were observed based on breed with levels of Beta MHC approximately 2 fold higher in the RAU, RA, LAU and LA (open full item for complete abstract)

Committee: Mamoru Yamaguchi (Advisor) Subjects: