Risk Factors for Sudden Cardiac Death in Patients with Chronic Kidney Disease

这是帕特里克·潘博士的K23申请书，他是一名肾脏科医生，也是 杜克大学医学中心。潘医生正在确立自己作为一名年轻调查员的地位- 慢性肾脏病(CKD)心源性猝死(SCD)定向临床研究。 通过有组织的职业发展计划，包括正规的遗传学教学培训 流行病学和数量遗传学，由一群有成就的高年级学生提供指导 调查人员和合作者，并进行原创性研究，检查独特的风险因素 在大量中度慢性肾脏病患者中，这一奖项将为潘博士提供 资源、培训和保护时间，以成为一名独立的临床研究人员 心脏肾脏疾病。潘博士的指导团队包括他的主要导师Laura Svetkey博士 (杜克大学高血压中心主任和杜克大学教师发展副主席 和两位共同导师，John Middleton博士(临床研究主任 杜克大学肾脏病学部)和Svati Shah博士(医学中心医学副教授 人类遗传学)。CKD影响着2900多万美国人；与普通人群相比， 这些患者患SCD的风险显著增加。CKD如何推广的确切性质 SCD的风险没有被很好地理解，传统的心血管风险因素不能充分解释 SCD风险。此应用程序的总体目标是识别具有高恶性风险的CKD患者。 心律失常和SCD，使这些患者可能成为干预的目标。中环 这一建议的假设是心脏传导问题与血清电解质有关 干扰、遗传影响和静息心电异常在决定 中度CKD(CKD 3-4期)患者的SCD风险。合并和链接大的潜在客户 包含35,000多名患者的临床数据和结果的纵向研究数据库 对于心血管疾病、遗传生物库和大量的医疗记录，该应用程序 包含以下具体目标：(1)评估血清电解质水平之间的关系 (2)评估中度CKD患者的(钾、钙、镁)和SCD风险 致心律失常基因常见变异与显著室性心动过速风险的关系 中度CKD患者的心律失常与SCD；以及(3)评估休息与 心电图室传导(QRS间期、QT间期)和心源性心脏病风险的心电测量 CKD的设置。由于高危CKD患者的SCD机制尚不清楚，因此 贡献将是巨大的，因为它可能阐明疾病的机制，提供新的工具 用于风险分层和监测，并确定预防SCD的具体潜在目标。

This is an application for a K23 for Dr. Patrick Pun, who is a nephrologist and Assistant Professor at Duke University Medical Center. Dr. Pun is establishing himself as a young investigator in patient- oriented clinical research on sudden cardiac death (SCD) in chronic kidney disease (CKD) patients. Through a structured career development plan including formal didactic training in genetic epidemiology and quantitative genetics, mentoring by a dedicated group of accomplished senior investigators and collaborators, and the conduct original research examining unique risk factors for SCD among a large population of patients with moderate CKD, this award will provide Dr. Pun the resources, training and protected time to become a an independent clinical researcher in the field of cardiorenal disease. Dr. Pun's mentoring team includes his primary mentor, Dr. Laura Svetkey (Director of the Duke Hypertension Center and the Vice Chair for Faculty development in the Duke Department of Medicine), and two co-mentors, Dr. John Middleton (Director of Clinical Research in the Duke Division of Nephrology) and Dr. Svati Shah (Associate Professor of Medicine, Center for Human Genetics). CKD affects more than 29 million Americans; compared the general population, these patients have a markedly increased risk of SCD. The precise nature of how CKD promotes SCD risk is not well understood, and traditional cardiovascular risk factors do not adequately explain SCD risk. The overall objective of this application is to identify CKD patients at high risk of malignant arrhythmias and SCD, so that these patients might be targeted for intervention. The central hypothesis of this proposal is that cardiac conduction problems related to serum electrolyte disturbances, genetic influences and resting ECG abnormalities play an important role in determining SCD risk in patients with moderate CKD (CKD stage 3-4). Combining and linking a large prospective longitudinal research database containing clinical data and outcomes from more than 35,000 patients with cardiovascular disease, a genetic biorepository, and extensive medical records, the application contains the following specific aims: (1) To evaluate associations between serum electrolyte levels (potassium, calcium and magnesium) and SCD risk in moderate CKD patients; (2) To evaluate associations between common variants in pro-arrhythmic genes and risk of significant ventricular arrhythmias and SCD in moderate CKD patients; and (3) To evaluate associations between resting ECG measurements of ventricular conduction (QRS duration, QTc interval) and SCD risk in the setting of CKD. Since SCD mechanisms in high-risk CKD patients are poorly understood, this contribution will be significant because it may elucidate mechanisms of disease, provide novel tools for risk stratification and monitoring, and identify specific potential targets for SCD prevention.