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.
View: Text | PDF
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

×

Figure 7

Patterns in expression of the chemokine receptor CX3CR1 and its ligand, fractalkine, suggest a role in T cell dynamics after reperfusion.

Options: View larger image (or click on image) Download as PowerPoint
Patterns in expression of the chemokine receptor CX3CR1 and its ligand, ...
(A) Chemokine receptor expression measured by MFI in T cells in NSTEMI patients (n = 5). Receptors eliminated at this stage indicated by asterisks and gray bars. (B) Chemokine receptor expression in CD4+ and CD8+ T cells in NSTEMI (n = 5) and STEMI (n = 5). (C) Pre-reperfusion expression of CX3CR1 in T cell subsets (n = 5 subset of STEMI group) correlates strongly with the mean drop in cells in STEMI patients (n = 59), according to linear regression and Pearson correlation coefficient. (D) Pre-reperfusion T cell surface expression of CX3CR1 in STEMI patients differs between subsets (Friedman test with Dunn’s multiple-comparisons test) (n = 5); box plots show median (central line), 25th and 75th percentiles (box limits), and range (error bars). (E) T cell subset CX3CR1 expression histograms (1 representative example of n = 5). (F) Serum levels of sFKN in STEMI patients, relative to pre-reperfusion level (one-way ANOVA, with Holm-Šídák multiple comparisons test) (n = 9). (G) Surface expression of CX3CR1 in CD4+CCR7– and CD8+CCR7– T cells (MFI relative to pre-reperfusion value). The results indicate an apparent drop in expression, which, given the findings in H, could also be due to ligand binding (Friedman test with Dunn’s multiple-comparisons test) (n = 5). (H) Preincubation of blood with recombinant fractalkine prior to CX3CR1 expression analysis indicates competition and reduced fluorescence on CCR7– (CX3CR1-expressing) T cells (MFI relative to baseline value) (n = 3). *P < 0.05, **P < 0.01. conc., concentration.