Renin-Angiotensin-Aldosterone System and Cardiac Arrhythmias in CKD

描述（由申请人提供）：这是Rajat Deo博士的K23奖申请，他提出使用严格的流行病学和生物统计学方法来了解肾素-血管紧张素-醛酮系统（RAAS）在慢性肾脏疾病（CKD）患者心律失常中的作用。该奖项将为Deo博士提供资源和保护时间，以实现以下职业发展目标：(1)成为心肾疾病和心律失常领域的独立临床研究人员；(2)成为运用因果推理方法和疾病亚临床指标的专家；(3)发展对评审过程和严格的队列研究设计至关重要的方法方面的专业知识。为了实现这些目标，Deo博士组建了一个指导团队，由他的赞助商和主要导师Harold Feldman博士（慢性肾功能不全队列[CRIC]的首席研究员和指导委员会主席）和两位共同导师Michael Shlipak博士（肾脏疾病心血管并发症领域的专家）和Marshall Joffe博士（高级生物统计学家）组成。最近的数据表明，CKD与心房和室性心律失常的风险增加有关；然而，这种倾向背后的机制尚不清楚。RAAS的激活可能介导CKD患者发生心律失常的风险。RAAS激活可以通过结构重塑过程和直接离子通道抑制影响心脏传导。这些结构和电生理变化可能是房性和室性心律失常的先兆。没有研究评估醛固酮在CKD中作为心律失常风险中介的作用。使用CRIC研究的数据，Deo博士将评估基线醛固酮与肾功能、心电图间隔和传导系统疾病标志物以及心律失常结果的关系。提出了三个具体目的：目的1：在CRIC研究中评估肾功能与醛固酮浓度的关系；目的2：确定循环醛固酮水平和肾功能与传导系统重构电生理参数的横切面和纵向关系；目的3：确定CRIC患者醛固酮水平升高和肾功能下降与房颤和心源性猝死的纵向关联。

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Rajat Deo, who proposes the use of rigorous epidemiologic and biostatistical methods to understand the role of the renin-angiotensin-aldosterone system (RAAS) in cardiac arrhythmias among people with chronic kidney disease (CKD). This award will allow Dr. Deo the resources and protected time to achieve the following career development goals: (1) to become an independent, clinical researcher in the field of cardiorenal disease and arrhythmias; (2) to become an expert in the application of causal inference methodology and sub-clinical measures of disease; and (3) to develop expertise in the methods critical to the adjudication process and rigorous design of cohort studies. To achieve these goals, Dr. Deo has assembled a mentoring team comprised of his sponsor and primary mentor, Dr. Harold Feldman (Principal Investigator and Chair of the Steering Committee for the Chronic Renal Insufficiency Cohort [CRIC]), and two co-mentors, Dr. Michael Shlipak (an expert in the field of cardiovascular complications of kidney disease) and Dr. Marshall Joffe (a senior biostatistician). Recent data demonstrate that CKD is associated with an increased risk of atrial and ventricular arrhythmias; however, the mechanisms underlying this predisposition remain unknown. Activation of the RAAS may mediate the risk of arrhythmias in patients with CKD. RAAS activation can affect cardiac conduction through both structural remodeling processes and direct ion channel inhibition. These structural and electrophysiological changes may be the precursors to atrial and ventricular arrhythmias. No study has evaluated the role of aldosterone as a mediator of arrhythmia risk in CKD. Using data from the CRIC study, Dr. Deo will evaluate baseline aldosterone with kidney function, electrocardiographic intervals and markers of conduction system disease, and arrhythmia outcomes. Three specific aims are proposed: Aim 1: To evaluate the association of kidney function with aldosterone concentrations in the CRIC study; Aim 2: To determine the cross-sectional and longitudinal associations of circulating aldosterone levels and kidney function with electrophysiological parameters of conduction system remodeling; and Aim 3: To determine the longitudinal associations of elevated aldosterone levels and reduced kidney function with atrial fibrillation and sudden cardiac death in CRIC. PUBLIC HEALTH RELEVANCE: Atrial fibrillation and sudden cardiac death risks are increased in patients with CKD, a highly prevalent disease in the United States. An improved understanding of the mechanisms implicated in these conditions could lead to important interventions and therapies to prevent the catastrophic complications of arrhythmias.