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 1

Lymphopenia after PPCI predicts higher mortality after PPCI in STEMI.

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Lymphopenia after PPCI predicts higher mortality after PPCI in STEMI. (A...
(A) Kaplan-Meier survival curves of 1,377 consecutive patients discharged alive following PPCI (follow up time 1,200 days). Patients were divided into three tertiles according to the minimum peripheral blood lymphocyte counts obtained during their admission. (B) Forest plot with outcome of stepwise Cox regression analysis for death over follow-up time, with covariates including age, sex, minimum lymphocyte tertile, previous angina, and serum creatinine (see Supplemental Methods for the full list of covariates) (n = 1,076). (C) Minimum lymphocyte count, divided by age group (<65: n = 756, 65–80: n = 472, >80: n = 149) and (D) Difference in minimum lymphocyte counts between survivors and non-survivors following PPCI, according to 3 age groups, compared using one-way ANOVA; ***P < 0.001.