Chemokine dynamics and the inflammatory response after cardiac injury

Problem/Background: The initial ischemic insult of a cardiac arrest (CA) episode triggers the inflammatory response, resulting in neurological, circulatory, and systemic ischemia-reperfusion injuries that are frequently fatal. More than 500,000 Americans suffer cardiac arrest annually, and despite improved cardiopulmonary resuscitation, post-resuscitation therapy, and cardiovascular systems of care, outcomes remain poor. Understanding molecular mechanisms contributing to survival after CA may lead to identification of therapeutic targets and improvement of outcomes. Chemotactic cytokines (chemokines) are secreted soluble or membrane-bound proteins that signal through G-protein coupled receptors to stimulate immune cell migration to the site of injury, acting as the first mobilizers of the inflammatory response. To our knowledge chemokine expression and function in cardiac arrest has not been examined. We measured levels of circulating chemokines in CA subjects as well as in Coronary Artery Bypass Graft (CABG) subjects before surgery. Approach: Study subjects admitted to intensive care after a CA episode and treated with therapeutic temperature management underwent phlebotomy at 6, 12, 24, 48, and 72 hours, and 7 days after return of spontaneous circulation (ROSC). Control subjects underwent CABG surgery with phlebotomy at pre-op, surgery, 4-8 hours, 24 hours, and 4 days postop. Blood samples were processed within 4 to 6 hours of collection. Platelets free plasma (PFP) was obtained from venous blood via consecutive centrifugations and stored at -800C. CCL2, CCL4, and CCL23 protein levels were determined using Human CCL2, CCL4, and CCL23 DuoSet ELISA (R&D Systems/biotechne) kits. Data analysis was performed with GraphPad Prism. Results: Each chemokine demonstrated unique dynamics in the context of cardiac arrest. Our results revealed large inter-individual variability, in accord with other analyte testing in this study group. All three chemokines were found at significantly elevated levels 24 hours post-ROSC as compared to control. CCL23 (MPIF-1, myeloid progenitor inhibitory factor-1), emerged as a protein of interest. This chemokine exhibits a specific time-dependent pattern associated with increased circulating levels at 24 to 48 hours post-ROSC. In our cohort, CCL23 levels are statistically significantly different between non-survivors (n=19) and survivors (n=23) at 48 hours post-ROSC, with non-survivor median CCL23 levels twice that seen in survivors. We also observed positive correlation between the number of white blood cells (WBCs) and CCL23 levels at 48 hours post-ROSC. Conclusion: Chemokine dynamics may provide insight into potential targets for treatment after cardiac arrest with focus on the inflammatory response in the first two days after injury. The current study provides an important contribution to our understanding of the role of chemokines and the inflammatory response after cardiac arrest. Further investigation into the expression locations and mechanisms of action of chemokines is warranted