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 Research and Public Health 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 5

Transcoronary gradients in cell counts, indicating loss of some cells across myocardial circulation.

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Transcoronary gradients in cell counts, indicating loss of some cells ac...
Blood was taken simultaneously from the aortic root and CS at the end of PPCI in a subset of STEMI patients (n = 12). Of these, n = 9 were anterior STEMI (samples taken at <45 minutes after reperfusion in n = 6; >45 minutes after reperfusion in n = 3) and n = 3 were inferior STEMI (all sampled at <45 minutes). (A) Percentage change in cell counts of leukocyte subsets between aorta (Ao) and CS for anterior MI with sampling at <45 minutes (n = 6). Negative values indicate a drop across myocardial circulation. Statistics refer to Wilcoxon signed rank test of aorta versus CS counts for the indicated populations. (B) Impact of sample timing and infarct location on transcoronary gradients. Statistics refer to difference between anterior infarcts with sampling before (n = 6) or after (n = 3) 45 minutes (Mann-Whitney U test). Note: Mean troponin T for anterior infarcts with sampling <45 minutes: 4,814 ± 1,811 ng/l, anterior infarcts with sampling >45 minutes: 9,705 ± 2,409 ng/l, inferior infarcts: 5,462 ± 2,890 ng/l, excluding larger infarcts in the anterior sampling <45 minutes cases as a possible cause for these findings. *P < 0.05.