My long-term research goal is to leverage translational research methodologies to develop novel and effective therapeutic strategies and improve outcomes in patients with ischemic heart disease. The primary focus of this proposal is to characterize pathophysiological mechanisms linking neutrophil activation and adverse outcomes after acute coronary syndrome and/or percutaneous coronary intervention (PCI). Much of our current knowledge about the potential role of neutrophils is based on observations from experimental models in mice, or microvascular models of inflammation. I propose to bridge the current gap in knowledge through detailed study of neutrophil biology and the association between neutrophil phenotype and adverse cardiovascular outcomes in patients who undergo clinically indicated PCI, a model of acute vascular injury. I further propose to use colchicine, an agent with direct neutrophil suppressive action, as a tool to elucidate the role of neutrophil activation during acute vascular injury. Colchicine may be particularly useful in the PCI setting due to its rapid onset of action and excellent side-effect profile at low doses, as well as its known mechanisms of action on neutrophil adhesion molecules. Patients referred for possible PCI will be randomized in a double-blinded fashion to placebo or colchicine (1.8mg PO over 1 hour prior to PCI). In this two by two study design (post- versus pre-PCI and colchicine versus placebo), the effect of PCI and study drug will be examined on neutrophil-specific biomarkers and neutrophil-endothelial cell and neutrophil-platelet interactions. I will also explore the association between neutrophil phenotype and adverse cardiovascular outcomes after PCI and the effects of colchicine on these outcomes. In-depth characterization of neutrophil biology in acute vascular injury will allow for exploration of new avenues in prevention and treatment, with a goal to identify novel selective targets that induce anti-inflammatory effects with minimal systemic immunosuppression. Characterization of post-cellular mediators via neutrophil extracellular trap and neutrophil-derived microparticle pathways may provide additional novel therapeutic targets. In addition, increased understanding of neutrophil biology gained in this proposal may provide novel insight into pathology of type 2 MI populations (e.g. demand ischemia in post-operative settings) and other atherosclerosis populations (e.g. peripheral artery disease). I completed a 5- year program at New York University (NYU) resulting in certification in general and Interventional Cardiology, as well as a Master's of Science degree in Clinical Investigation. A VA Career Development Award will provide me with the stepping stone on which to advance to investigative independence, by supporting me through a series of courses and providing protected time for structured tutorials on the effective utilization of translational approaches an topics in inflammation. The strong environment and resources of the Manhattan VA and its academic affiliates, the Clinical and Translational Science Institute and the Cardiovascular Clinical Research Center at NYU, will allow me to successfully execute the career development plan outlined in this proposal. This proposal features a multi-disciplinary approach, with support from experts in cardiology and rheumatology in both basic and clinical science, to reduce adverse outcomes after PCI. Such cross-disciplinary collaboration is necessary to effectively conduct translational research and will help prepare me for my career as a successful independent investigator.

Public Health Relevance

Heart disease remains the leading cause of death for both men and women. Inflammation in the arteries of the heart may increase the risk of cardiac death. The proposed research seeks to better understand the role of neutrophils, the most common type of inflammatory white blood cell in the body, in the damage caused by opening up a blockage in the arteries of the heart. This research also seeks to identify the potential beneficial role of a safe medication, colchicine which has direct effects on neutrophils and has been used for the treatment of gout for more than 100 years, on reducing this damage to the heart. With its quick onset of action and excellent safety profile, colchicine may have the potential to reduce risk of cardiac death.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
5IK2CX001074-02
Application #
9210547
Study Section
Cardiovascular Studies B (CARB)
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
VA Medical Center
Department
Type
Independent Hospitals
DUNS #
070501002
City
New York
State
NY
Country
United States
Zip Code
10010
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