The Fractalkine Receptor CX3CR1 Links Lymphocyte Kinetics in CMV-Seropositive Patients and Acute Myocardial Infarction With Adverse Left Ventricular Remodeling.

Luke Spray,Peter P Rainer,Ashfaq Mohammed,Catherine Park,Karim Bennaceur,Pedram Panahi,Verena M Stangl,Gustavo Campos Ramos,Stephen Boag,Konstantinos Stellos,Ioakim Spyridopoulos,Suzanne Cormack,Ulrich Hofmann,Lavinia Rech,Kateryna Sopova,Gavin Richardson

doi:10.3389/fimmu.2021.605857

Abstract

AimsLatent cytomegalovirus (CMV) infection is associated with adverse cardiovascular outcomes. Virus-specific CX3CR1+ effector memory T-cells may be instrumental in this process due to their pro-inflammatory properties. We investigated the role of CX3CR1 (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 ResultsWe 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 CX3CR1 were depleted predominantly in CMV-seropositive patients. During ischaemia/reperfusion, a drop in CX3CR1+ 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.ConclusionWe 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 CX3CR1+ T-cells may contribute to adverse remodeling, suggesting a pro-inflammatory pathomechanism which presents a novel therapeutic target.

Highlights

The immunological component of atherosclerosis and coronary artery disease has garnered increasing interest in the last decade
We investigated the role of CX3CR1 in CMV-related lymphocyte kinetics and cardiac remodeling in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention
During ischaemia/reperfusion, a drop in CX3CR1+ T-lymphocytes was significantly linked with microvascular obstruction in CMV+ patients, suggesting increased fractalkine-receptor interaction

Summary

Introduction

The immunological component of atherosclerosis and coronary artery disease has garnered increasing interest in the last decade. The CANTOS trial demonstrated the potential for targeting specific pathways in the innate immune system [1], but targeted inhibition of the adaptive immune system has not yet yielded such favourable results [4]. Our group has shown that T-lymphocytes contribute to myocardial ischaemia/reperfusion injury after primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI), with the fractalkine receptor, CX3CR1, playing a central role [5]. CMV, a ubiquitous herpes virus, inflates the T-lymphocyte compartment with CMV-specific, cytotoxic T-cells [5, 7,8,9], which have been shown to induce endothelial damage through induction of fractalkine (the CX3CR1 ligand) [9, 10]

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