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.
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.
|Shah, Binita; McDonald, Daniel; Paone, Darien et al. (2018) Outcomes after transcatheter aortic valve replacement in patients with low versus high gradient severe aortic stenosis in the setting of preserved left ventricular ejection fraction. J Interv Cardiol 31:849-860|
|Krasnokutsky, Svetlana; Romero, Aaron Garza; Bang, Daisy et al. (2018) Impaired arterial responsiveness in untreated gout patients compared with healthy non-gout controls: association with serum urate and C-reactive protein. Clin Rheumatol 37:1903-1911|
|Ganguzza, Lisa; Ngai, Calvin; Flink, Laura et al. (2018) Association between diet quality and measures of body adiposity using the Rate Your Plate survey in patients presenting for coronary angiography. Clin Cardiol 41:126-130|
|Smilowitz, Nathaniel R; Subramanyam, Pritha; Gianos, Eugenia et al. (2018) Treatment and outcomes of type 2 myocardial infarction and myocardial injury compared with type 1 myocardial infarction. Coron Artery Dis 29:46-52|
|Slobodnick, Anastasia; Shah, Binita; Krasnokutsky, Svetlana et al. (2018) Update on colchicine, 2017. Rheumatology (Oxford) 57:i4-i11|
|Schoenfeld, Matthew S; Kassas, Ibrahim; Shah, Binita (2018) Transradial Artery Access in Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction and Cardiogenic Shock. Curr Treat Options Cardiovasc Med 20:11|
|Villablanca, Pedro; Shah, Binita (2018) Size Matters: Moving Toward a Slender Transradial Artery Approach. Cardiovasc Revasc Med 19:401-402|
|Shah, Binita; Baber, Usman; Pocock, Stuart J et al. (2017) White Blood Cell Count and Major Adverse Cardiovascular Events After Percutaneous Coronary Intervention in the Contemporary Era: Insights From the PARIS Study (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients Registry). Circ Cardiovasc Interv 10:|
|Seto, Arnold H; Dehghani, Payam; Shah, Binita et al. (2017) Late breaking trials of 2016 in coronary artery disease: Commentary covering SCAI, ACC, TCT, EuroPCR, ESC, and AHA. Catheter Cardiovasc Interv 89:1028-1034|
|Teperman, Jacob; Carruthers, David; Guo, Yu et al. (2017) Relationship between neutrophil-lymphocyte ratio and severity of lower extremity peripheral artery disease. Int J Cardiol 228:201-204|
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