The Fractalkine Receptor CX3CR1 Links Lymphocyte Kinetics in CMV-Seropositive Patients and Acute Myocardial Infarction With Adverse Left Ventricular Remodeling
Luke Spray, Catherine Park, Suzanne Cormack, Ashfaq Mohammed, Pedram Panahi, Stephen Boag, Karim Bennaceur, Kateryna Sopova, Gavin D. Richardson, Verena Stangl, Lavinia Rech, Peter P. Rainer, Gustavo Ramos, Ulrich Hofmann, Konstantinos Stellos, Ioakim Spyridopoulos
Abstract
Aims Latent cytomegalovirus (CMV) infection is associated with adverse cardiovascular outcomes. Virus-specific CX 3 CR1 + effector memory T-cells may be instrumental in this process due to their pro-inflammatory properties. We investigated the role of CX 3 CR1 (fractalkine receptor) in CMV-related lymphocyte kinetics and cardiac remodeling in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). Methods and Results We retrospectively analysed lymphocyte count, troponin, and survival in 4874 STEMI/pPCI patients, evaluated lymphocyte kinetics during reperfusion in a prospective cohort, and obtained sequential cardiac MRI (cMRI) to assess remodeling. Pre-reperfusion lymphopenia independently predicted mortality at 7.5 years. Prior to reperfusion, CCR7 + T-lymphocytes appeared to be depleted. After reperfusion, T-lymphocytes expressing CX 3 CR1 were depleted predominantly in CMV-seropositive patients. During ischaemia/reperfusion, a drop in CX 3 CR1 + T-lymphocytes was significantly linked with microvascular obstruction in CMV+ patients, suggesting increased fractalkine-receptor interaction. At 12 weeks, CMV+ patients displayed adverse LV remodeling. Conclusion We show that lymphopenia occurs before and after reperfusion in STEMI by different mechanisms and predicts long-term outcome. In CMV+ patients, increased fractalkine induction and sequestration of CX 3 CR1 + T-cells may contribute to adverse remodeling, suggesting a pro-inflammatory pathomechanism which presents a novel therapeutic target.