Chronic kidney disease is a powerful risk factor for subclinical left ventricular systolic dysfunction and incident heart failure, but the mechanisms of these relationships remain incompletely understood. The inflammasome drives renal and cardiac inflammation by activating the inflammatory cytokines interleukin-1? and interleukin-18 and the pyroptotic protein gasdermin-D. In patients with systolic heart failure or coronary artery disease, pharmacologic interleukin-1? blockade improves left ventricular systolic function and maximal exercise capacity and is associated with a trend towards fewer heart failure hospitalizations. Exogenous interleukin-18 administration to wild-type mice impairs left ventricular systolic function whereas blocking interleukin-18 after experimental myocardial infarction preserves left ventricular systolic function. Furthermore, interleukin-1??s cardiodepressant effects are mediated in part by interleukin-18, suggesting that simultaneous blockade of both cytokines would confer additional benefit beyond targeting either cytokine alone. The broad goal of this application is to prepare the principal investigator, Dr. Leo Buckley PharmD, for a career as an independent, patient-oriented researcher who studies cardiovascular pharmacology with a specific interest in preventing and treating heart failure by identifying and targeting pathways that regulate myocardial structure and function. In addition to focused coursework and seminars, Dr. Buckley will complete a series of patient-oriented studies under the guidance of an expert mentoring committee to test the hypothesis that inflammasome activity contributes to incident heart failure risk in adults with chronic kidney disease by promoting left ventricular systolic dysfunction. He will address two specific aims: (1) that increased inflammasome activity associates with left ventricular systolic dysfunction and increased risk of incident heart failure in older adults; and (2) To test the hypothesis that colchicine improves left ventricular systolic function and reduces inflammasome activity in patients with uremic cardiomyopathy. These studies will improve our knowledge of and spur further investigations into the role of inflammatory cytokines in the pathogenesis of subclinical left ventricular dysfunction and heart failure. By the conclusion of the award, Dr. Buckley will have established an independent, patient-oriented cardiovascular pharmacology research program.

Public Health Relevance

Many patients with chronic kidney disease develop heart failure, but the underlying causes remain unclear. Animal models of human disease suggest that the inflammasome may contribute to the development of heart failure in patients with chronic kidney disease. An epidemiologic study and a clinical trial will be conducted to improve our understanding of the role of inflammasome activity in the development of heart failure among adults with chronic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23HL150311-01A1
Application #
10055649
Study Section
NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
Program Officer
Redmond, Nicole
Project Start
2020-08-01
Project End
2025-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115