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

描述(申请人提供)：这是杜克大学医学中心的肾科医生兼助理教授帕特里克·潘博士的K23申请表。潘博士在以患者为导向的慢性肾脏疾病(CKD)患者心源性猝死(SCD)临床研究中确立了自己作为年轻研究员的地位。通过一个有组织的职业发展计划，包括正规的遗传流行病学和数量遗传学教学培训，由一群经验丰富的资深研究人员和合作者组成的专门团队的指导，以及在大量中度CKD患者中进行独特的SCD风险因素的原创研究，这个奖项将为潘博士提供资源、培训和保护时间，使其成为心肾疾病领域的独立临床研究人员。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医学部教研室副主任)，以及两位共同导师，John Middleton博士(杜克大学肾脏病学部临床研究主任)和Svati Shah博士(人类遗传学中心医学副教授)。CKD影响着2900多万美国人；与普通人群相比，这些患者患SCD的风险明显增加。CKD如何促进SCD风险的确切本质尚不清楚，传统的心血管风险因素不能充分解释SCD风险。这项应用的总体目标是确定CKD患者的恶性心律失常和SCD的高危程度，以便这些患者可能成为干预的目标。这一建议的中心假设是，与血清电解质紊乱、遗传影响和静息心电图异常有关的心脏传导问题在确定中度CKD(CKD 3-4期)患者的SCD风险方面发挥着重要作用。结合和链接包含超过35,000名心血管疾病患者的临床数据和结果的大型前瞻性纵向研究数据库、遗传生物库和大量医疗记录，该应用包含以下具体目标：(1)评估中度CKD患者的血清电解质水平(钾、钙和镁)与SCD风险之间的关联；(2)评估中度CKD患者中致心律失常基因的常见变异与严重室性心律失常和SCD风险之间的关联；以及(3)评估静息心电图对CKD患者的室传导(QRS时限、QTC间期)和SCD风险之间的关联。由于高危CKD患者的SCD机制知之甚少，这一贡献将是重要的，因为它可能阐明疾病的机制，为风险分层和监测提供新的工具，并确定SCD预防的特定潜在靶点。

DESCRIPTION (provided by applicant): 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 identif 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 potentia targets for SCD prevention.