Though sudden cardiac death is the single leading cause of mortality in dialysis patients, no effective or practical treatment presently exists. The long term project goal is to identify modifiable nutritional factors that can reduce sudden cardiac death and other cardiovascular event rates in kidney disease patients. Long chain omega-3 polyunsaturated fatty acids (n-3 PUFA) modulate cardiac electrophysiology and may reduce sudden cardiac death risk. The project's central hypothesis is that low n-3 PUFA serum content in hemodialysis patients results in an increased susceptibility to ventricular arrhythmias and a higher rate of sudden cardiac death. Though project investigators have generated pilot data supporting the central hypothesis, statistical power and generalizability are limited. The Accelerated Mortality on Renal Replacement (ArMORR) cohort, which includes over 10,000 nationally representative incident hemodialysis patients, presents a unique and compelling opportunity to test the study hypothesis because it offers (i) generalizability and ample statistical power and (ii) an unrivalled opportunity to study sudden cardiac death during the highly risky early months of hemodialysis while (iii) avoiding survival bias. The novel hypothesis will be tested with the following specific aim: To establish the relationship between serum long chain omega-3 polyunsaturated fatty acid content and sudden cardiac death risk in incident hemodialysis patients. Using a nested case- control design, baseline serum n-3 PUFA in total lipids and lipid fractions (i.e. triglycerides, phospholipids) will be measured by gas chromatography in 200 ArMORR patients who died of sudden cardiac death within the first year of hemodialysis (cases) and 400 matched ArMORR patients who survived (controls). Relative and absolute serum n-3 PUFA content will both be reported, thus offering new insights into n-3 PUFA as a biomarker. Odds ratios for sudden death risk will be calculated. The project investigators are singularly qualified to undertake this project, having unique research experience in this area. The proposed project's approach is exploratory and paradigm-shifting as it seeks to identify in dialysis patients a biologically plausible and easily reversible nutritional cause for sudden cardiac death that has never previously been examined. This will be the first study to characterize fatty acid (including n-3 PUFA) content in a nationally representative dialysis population, information that can then be applied to other disease states. Project investigators expect it will also identify a strong and independent inverse relationship between serum n-3 PUFA content and sudden cardiac death as well as the best serum n-3 PUFA sudden death biomarker. This, in turn, will provide critical information to help establish a randomized n-3 PUFA interventional trial evaluating the under-studied end point of sudden cardiac death in dialysis patients.

Public Health Relevance

Omega-3 fatty acids have been shown to reduce the risk of sudden cardiac death, the leading cause of death in hemodialysis patients. This project is designed to determine if low blood levels of omega-3 fatty acids in hemodialysis patients are linked to higher rates of sudden cardiac death. Demonstrating this will support a strategy of trying to reduce sudden cardiac death risk in hemodialysis patients by giving them fish oil supplements.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK084403-02
Application #
8092478
Study Section
Special Emphasis Panel (ZRG1-DKUS-G (51))
Program Officer
Kusek, John W
Project Start
2010-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$227,869
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Friedman, Allon N; Yu, Zhangsheng; Denski, Cheryl et al. (2013) Fatty acids and other risk factors for sudden cardiac death in patients starting hemodialysis. Am J Nephrol 38:12-8
Friedman, Allon N; Yu, Zhangsheng; Tabbey, Rebeka et al. (2013) Inverse relationship between long-chain n-3 fatty acids and risk of sudden cardiac death in patients starting hemodialysis. Kidney Int 83:1130-5
Friedman, Allon N; Yu, Zhangsheng; Tabbey, Rebeka et al. (2012) Low blood levels of long-chain n-3 polyunsaturated fatty acids in US hemodialysis patients: clinical implications. Am J Nephrol 36:451-8