T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients
Stephen E. Boag, … , Bernard Keavney, Ioakim Spyridopoulos
Stephen E. Boag, … , Bernard Keavney, Ioakim Spyridopoulos
Published July 13, 2015
Citation Information: J Clin Invest. 2015;125(8):3063-3076. https://doi.org/10.1172/JCI80055.
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Clinical Medicine Cardiology

T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients

Abstract

BACKGROUND. Lymphocytes contribute to ischemia/reperfusion (I/R) injury in several organ systems, but their relevance in ST elevation myocardial infarction (STEMI) is unknown. Our goal was to characterize lymphocyte dynamics in individuals after primary percutaneous coronary intervention (PPCI), assess the prognostic relevance of these cells, and explore mechanisms of lymphocyte-associated injury.

METHODS. Lymphocyte counts were retrospectively analyzed in 1,377 STEMI patients, and the prognostic relevance of post-PPCI lymphopenia was assessed by Cox proportional hazards regression. Blood from 59 prospectively recruited STEMI patients undergoing PPCI was sampled, and leukocyte subpopulations were quantified. Microvascular obstruction (MVO), a component of I/R injury, was assessed using MRI.

RESULTS. In the retrospective cohort, lymphopenia was associated with a lower rate of survival at 3 years (82.8% vs. 96.3%, lowest vs. highest tertile; hazard ratio 2.42). In the prospective cohort, lymphocyte counts fell 90 minutes after reperfusion, primarily due to loss of T cells. CD8+ T cells decreased more than CD4+ T cells, and effector subsets exhibited the largest decline. The early decrease in effector T cell levels was greater in individuals that developed substantial MVO. The drop in T cell subsets correlated with expression of the fractalkine receptor CX3CR1 (r2 = 0.99, P = 0.006). Serum fractalkine concentration peaked at 90 minutes after reperfusion, coinciding with the T cell count nadir.

CONCLUSIONS. Lymphopenia following PPCI is associated with poor prognosis. Our data suggest that fractalkine contributes to lymphocyte shifts, which may influence development of MVO through the action of effector T cells.

TRIAL REGISTRATION. Not applicable.

FUNDING. British Heart Foundation (FS/12/31/29533) and National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre.

Authors

Stephen E. Boag, Rajiv Das, Evgeniya V. Shmeleva, Alan Bagnall, Mohaned Egred, Nicholas Howard, Karim Bennaceur, Azfar Zaman, Bernard Keavney, Ioakim Spyridopoulos

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Figure 8

Example of gating strategy for eight-color flow cytometry assay.

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Example of gating strategy for eight-color flow cytometry assay. Lymphoc...
Lymphocytes and monocytes were gated on their characteristic scatter patterns. Lymphocytes were classified based on CD3 expression to identify T cells, then divided into CD4+ and CD8+ T cells, prior to separation into their four main subsets of naive (TN), central memory (TCM), effector memory (TEM), and TEMRA cells. Each subset was also analyzed for expression of the differentiation marker CD27. CD3– lymphocytes were characterized as NK cells or B cells based on expression of CD16 and CD56. Monocytes were subdivided by expression of CD16.