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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK089118-03
Application #
8332326
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M2))
Program Officer
Rankin, Tracy L
Project Start
2010-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$154,235
Indirect Cost
$11,425
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Patel, Parin J; Borovskiy, Yuliya; Killian, Anthony et al. (2016) Optimal QT interval correction formula in sinus tachycardia for identifying cardiovascular and mortality risk: Findings from the Penn Atrial Fibrillation Free study. Heart Rhythm 13:527-35
Deo, Rajat; Shou, Haochang; Soliman, Elsayed Z et al. (2016) Electrocardiographic Measures and Prediction of Cardiovascular and Noncardiovascular Death in CKD. J Am Soc Nephrol 27:559-69
Deo, Rajat; Norby, Faye L; Katz, Ronit et al. (2016) Development and Validation of a Sudden Cardiac Death Prediction Model for the General Population. Circulation 134:806-16
Deo, Rajat; Katz, Ronit; de Boer, Ian H et al. (2015) Fibroblast growth factor 23 and sudden versus non-sudden cardiac death: the Cardiovascular Health Study. Am J Kidney Dis 66:40-6
Deo, Rajat; Yang, Wei; Khan, Abigail M et al. (2014) Serum aldosterone and death, end-stage renal disease, and cardiovascular events in blacks and whites: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study. Hypertension 64:103-10
Deo, R; Nalls, M A; Avery, C L et al. (2013) Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants. Heart Rhythm 10:401-8
Magnani, Jared W; Wang, Na; Nelson, Kerrie P et al. (2013) Electrocardiographic PR interval and adverse outcomes in older adults: the Health, Aging, and Body Composition study. Circ Arrhythm Electrophysiol 6:84-90
Ky, Bonnie; Shults, Justine; Keane, Martin G et al. (2013) FGF23 modifies the relationship between vitamin D and cardiac remodeling. Circ Heart Fail 6:817-24
Deo, Rajat; Varosy, Paul D (2012) Invited commentary-Global arrhythmia burden: the public health implications of the rise in atrial fibrillation comment on "The increasing burden of atrial fibrillation compared with heart failure and myocardial infarction". Arch Intern Med 172:741-2
Mathew, Jehu; Katz, Ronit; St John Sutton, Martin et al. (2012) Chronic kidney disease and cardiac remodelling in patients with mild heart failure: results from the REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction (REVERSE) study. Eur J Heart Fail 14:1420-8

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