Patient with ST-segment elevation myocardial infarction (STEMI) have a high risk of recurrent major adverse cardiovascular events (MACE) (approximately 20% at three years). Vascular inflammation plays a key role in this pathogenesis of recurrent MACE, and neutrophils are the most abundant of inflammatory cells. Neutrophils adhere to inflamed or injured endothelium, migrate into the vessel wall, release proteolytic enzymes that can lead to erosion or rupture of plaque, and activate the inflammasome and synthesis of interleukin-1?, a known target for therapy for secondary prevention of cardiovascular events. Neutrophils also release neutrophil extracellular traps (NETs) and microparticles, both of which may promote sustained inflammatory signaling and thrombus generation even after neutrophil death. Colchicine is a safe, well-tolerated anti-inflammatory agent that preferentially accumulates in neutrophils compared with other inflammatory cells. Colchicine inhibits chemotaxis, endothelial adhesion, and extravasation of neutrophils at sites of endothelial injury or inflammation; suppresses the inflammasome- mediated production of interleukin-1?; and reduces inflammation and MACE in patients with stable heart disease. The effects of colchicine in patients with STEMI, however, is not known. The CLEAR SYNERGY study is a multicenter randomized trial of colchicine versus placebo in 4000 STEMI patients treated with PCI. This proposal leverages the CLEAR SYNERGY study to obtain blood samples for neutrophil characterization.
The aims of this proposal are to 1) assess the effect of colchicine on neutrophil activation, including neutrophil- driven responses such as NETs and microparticles, 2) examine the clinical and genetic factors that may determine heterogeneity of treatment response based on neutrophil activity markers, and 3) develop a risk score based on markers of neutrophil activity to predict occurrence of MACE over 3 years after STEMI, and assess the impact of colchicine on the relation between this risk score and MACE. By utilizing blood specimens derived from CLEAR SYNERGY study participants immediately after STEMI and on 3-month follow-up, this proposal offers the opportunity to provide mechanistic insight into the findings of this large randomized trial; cost-effectively add scientific value independent of the CLEAR SYNTERGY study findings; potentially promote discovery of novel selective targets and therapeutic options to reduce cardiovascular inflammation with minimal immunosuppression; and foster a personalized medicine approach to therapy after STEMI. Finally, findings from this study may also open a door to novel therapeutic strategies in other settings of cardiovascular inflammation and injury (e.g., peripheral artery disease, stroke) and other disease states in which neutrophils play a pivotal role (e.g., vasculitis, wound healing).
Heart disease remains the leading cause of death, and inflammation after a heart attack increases the risk of recurrent heat attacks, stroke, and 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 risk of these adverse cardiovascular events after a heart attack. This research also seeks to understand 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 the residual risk after a heart attack.
