Inflammasome Activity as a Potential Contributor to Uremic Cardiomyopathy

PROJECT SUMMARY
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-1β and interleukin-18
and the pyroptotic protein gasdermin-D. In patients with systolic heart failure or coronary artery disease,
pharmacologic interleukin-1β 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-1β’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.

Grant Number: 3K23HL150311-05S1
NIH Institute/Center: NIH
Principal Investigator: Leo Buckley