Background: Hypertrophic Cardiomyopathy (HCM) and Long QT Syndrome (LQTS) are genetic cardiovascular diseases that cause sudden cardiac death. When an individual is diagnosed with an inherited disease such as HCM/LQTS it is critical that their biological relatives are notified of their increased risk. Newly diagnosed individuals in turn notify other at-risk family members through a successive process called cascade screening. This facilitates screening of at-risk biological relatives through genetic testing and/or clinical testing, and treatment for HCM/LQTS prior to development of life-threatening complications. However, for cascade screening to detect all potential cases the disease risk must be effectively communicated to all at-risk relatives. The responsibility for notifying family members of this risk largely falls to the first person diagnosed in the family (proband). Empiric evidence suggests that around half of at-risk relatives are not screened in accordance with cascade screening recommendations, potentially due to information about HCM/LQTS risk not being communicated effectively in their families. Factors have been identified that influence communication about genetic risk in families with non-cardiac disease; however, it is not known if or how these factors apply in families with genetic cardiac disease. These include network factors, which describe characteristics of relationships between family members and non-network factors, which describe characteristics of individuals including individual factors, disease factors, and sociocultural factors. There is a critical need to understand communication in families with HCM/LQTS in order to facilitate effective genetic risk communication in families, improve adherence to cascade screening recommendations, and prevent death and complications from cardiovascular diseases. Objectives: The purpose of this study was to improve our understanding of the relationships among network and non-network factors and communication of genetic risk for HCM/LQTS between probands and their relatives. I proposed the following aims: Aim 1: Describe family social network structures and communication paths about risk for HCM/LQTS from probands to their relatives. Aim 2: Identify which network and non-network factors are associated with who is told about risk for HCM/LQTS. Methods: The sample for this study included individuals with HCM or LQTS recruited through the University of Iowa Cardiology Clinics (UI) and the University of Wisconsin Inherited Arrhythmia Clinic (UW). Data were collected using a structured interview, family pedigree, and survey. Analysis included egocentric social network analysis, descriptive, bivariate, and multilevel logit regression modeling. Results: Participants in this study had an average of 24 living at-risk relatives in their families. Overall, just over half (52%) of these at-risk relatives had been reported to have been told about their risk. However, within families, the percentage of relatives told about their risk ranged from 0%-100%. Ninety percent of first-degree relatives were told about their risk, 61% of second-degree relatives were told and 33% of third-degree relatives were told. Recruitment site affiliation was determined to be a confounder and so analyses were calculated separately for UI and UW. In both the UI and UW samples, network factors including closer geographic distance, increased emotional closeness, increased relationship quality, increased frequency of communication, higher betweenness centrality, and closer degree of biological relation were independently associated with increased odds of communication of risk. In the UI sample, non-network factors that were independently associated with increased odds of communication of risk included younger age at diagnosis; having LQTS; having positive genetic test results; having an ICD; younger current age; being female; having increased role limitations due to physical functioning; feeling anxious about telling family members about risk; feeling communication was a burden; feeling that communication was a responsibility or duty; being happy to be able to share important information; and identifying financial issues, pregnancies, or upcoming marriages as playing a role in communication. In a multivariate model, increased frequency of communication, closer degree of biological relation, having an ICD, and identifying financial issues and pregnancies as contributors to communication were significantly associated with communication of genetic risk information. In the UW sample, non-network factors that were independently associated with increased odds of communication of risk included younger age, decreased emotional wellbeing, increased role limitations due to emotional wellbeing, and decreased energy and fatigue. In a multivariate model, increased frequency of communication and closer degree of biological relation were significantly associated with communication. Although over half of at-risk relatives were told about their risk, just over half of those (53.8%) were reported to have screened for disease, which represents 27% of all at-risk relatives. Of those tested, 35% were reported as diagnosed with HCM/LQTS. Conclusion: Communication of genetic risk for HCM/LQTS in families is inadequate and contributes to the problem of relatives not being screened for disease. Insight on the factors that influence communication in families at risk of sudden cardiac death can guide development of interventions, policies, and future research aimed at improving genetic risk communication and cascade screening, and preventing death and complications from inherited cardiac diseases. This research is applicable for genetic conditions where population based screening methods are not effective and rely on families to communicate risk and need for screening.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22335号 / 医博第4576号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 岩田 想, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23423号 / 医博第4768号 / 新制||医||1053(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邊 直樹, 教授 湊谷 謙司, 教授 山下 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Atrial fibrillation, long QT syndrome, and Middle East Respiratory Syndrome are three deadly human diseases for which genetic animal models are needed. From elucidating disease pathogenesis to facilitating the development of treatments, animal models are crucial for studying human disease. One of the most effective ways to generate specific animal models is through genetic modification. Historically, mice have been most widely used as genetically modified models, despite a number of limitations. New gene editing technologies such as CRISPR/Cas9 have made developing alternative genetic models that better recapitulate some human diseases better and more feasible. In this thesis, I describe my efforts to develop genetically modified goat and hamster models for atrial fibrillation and long QT syndrome, and genetically modified hamster models for Middle East Respiratory Syndrome. For long QT syndrome model development, I knocked out the KCNQ1 gene in goat fetal fibroblast cells and baby hamster kidney cells using the CRIPSR/Cas9 system. The knockout results in loss-of-function mutations, a known cause of human long QT syndrome. The edited goat fibroblast cells will be nuclear donors for future cloning experiments to produce live goats possessing the KCNQ1 knockout. The CRISPR gene targeting sgRNA/Cas9 vector, specific for the hamster KCNQ1, has been used for pronuclear injections to produce KCNQ1 knockout hamsters. For atrial fibrillation model development, I designed a single-stranded donor oligonucleotide that generates a KCNQ1 gainof-function mutation resulting in the disease. This oligonucleotide was injected into hamster embryos along with the KCNQ1 sgRNA/Cas9-expressing vector to generate hamsters containing the gain-of-function mutation. Finally, for Middle East Respiratory Syndrome model development, I established a breeding colony of human DPP4 transgenic hamsters in the STAT2 knockout background. Human DPP4 transgenic hamsters are susceptible to MERS-CoV infection, showing mild clinical signs and allowing viral replication in lung tissue. Giving these hamsters a STAT2 knockout background should promote a more severe disease progression. For all three diseases, the foundations for the development of genetic animal models have been laid.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19609号 / 医博第4116号 / 新制||医||1015(附属図書館) / 32645 / 京都大学大学院医学研究科医学専攻 / (主査)教授 岩井 一宏, 教授 小杉 眞司, 教授 瀬原 淳子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13232号 / 論医博第2172号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 江藤 浩之, 教授 木村 剛 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Long QT syndrome (LQTS) can present with syncope and seizure-like activity in the setting of torsades de pointes (TdP) with hemodynamic instability. Electrolyte abnormalities and medications can predispose to TdP in the setting of latent LQTS. An implantable cardioverter defibrillator (ICD) is needed if patients with TdP continue to be symptomatic despite medical treatment. We report a case of a patient who presented with seizures and was found to have prolonged corrected QT interval (QTc). During her admission, she was treated with ondansetron. She went into torsades de pointes and continued to have prolonged QTc. She underwent implantable cardioverter defibrillator (ICD) placement and remains asymptomatic to date.

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