Renin-Angiotensin-Aldosterone System and Cardiac Arrhythmias in CKD

描述(申请人提供)：这是对Rajat Deo博士的K23奖项的申请，他建议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-醛固酮系统(RAAS)在慢性肾脏疾病(CKD)患者心律失常中的作用。这一奖项将使Deo博士拥有资源和受保护的时间，以实现以下职业发展目标：(1)成为心脏肾脏疾病和心律失常领域的独立临床研究人员；(2)成为因果推断方法和疾病亚临床测量应用方面的专家；以及(3)发展对队列研究的裁决过程和严格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，成员包括他的赞助人和主要导师Harold Feldman博士(慢性肾功能不全队列[CRIC]指导委员会主席兼首席研究员)，以及两位共同导师Michael Shlipak博士(肾脏疾病心血管并发症领域的专家)和马歇尔·乔菲博士(资深生物统计学家)。最近的数据表明，CKD与房性和室性心律失常的风险增加有关；然而，这种易感性的机制仍然不清楚。RAAS的激活可能介导CKD患者发生心律失常的风险。RAAS的激活可通过结构重塑过程和直接离子通道抑制来影响心脏传导。这些结构和电生理改变可能是房性和室性心律失常的先兆。还没有研究评估醛固酮作为慢性肾脏病心律失常风险的介体的作用。利用CRIC研究的数据，迪奥博士将用肾功能、心电间期和传导系统疾病的标记物以及心律失常结果来评估基线的醛固酮水平。提出了三个具体目标：目的1：评价CRIC研究中肾功能与醛固酮浓度的关系；目的2：确定循环中的醛固酮水平和肾功能与传导系统重构的电生理参数的横断面和纵向关系；以及目标3：确定CRIC中醛固酮水平升高和肾功能降低与房颤和心脏性猝死的纵向关系。 公共卫生相关性：CKD患者的房颤和心脏性猝死风险增加，CKD在美国是一种高度流行的疾病。更好地了解这些情况所涉及的机制可能会导致重要的干预和治疗，以预防心律失常的灾难性并发症。

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.