The role of T lymphocytes in myocardial ischaemia/reperfusion injury

Abstract

Myocardial infarction is the greatest cause of mortality worldwide, and a source of considerable morbidity. Treatment of STCelevation MI (STEMI) has improved enormously with the advent of primary percutaneous coronary intervention (PPCI), but ischaemia/reperfusion (I/R) injury remains an important complication. Evidence from animal studies points to a role for lymphocytes, and in particular T cells, in myocardial I/R injury, but this has not yet been studied in humans. The goal of my PhD was to investigate this phenomenon in human patients treated with PPCI, with particular emphasis on T cell kinetics, their relationship to I/R injury, and the potential mechanisms involved. I retrospectively analysed a large database of MI patients treated with PPCI. I demonstrated that lymphopaenia during admission was an independent predictor of increased longCterm mortality, confirming the prognostic relevance of lymphocytes in this setting for the first time. I then studied a prospectively recruited cohort of STEMI patients, determining lymphocyte subset kinetics with detailed flowCcytometric analysis. T cells were acutely depleted from the circulation within minutes of reperfusion, with highly differentiated effector cells showing the greatest changes. TransCcoronary gradients suggested some cells were sequestered into the reperfused myocardium. Cardiac MRI analysis revealed a significant relationship between postCreperfusion effector T cell kinetics and microvascular obstruction (MVO), a component of I/R injury, raising the possibility of a mechanistic link. This discovery was driven primarily by positive findings in cytomegalovirus seropositive patients, who had higher percentages of highly differentiated T cells. Analysis of chemokine receptors subsequently identified CX3CR1, with its ligand fractalkine, as the prime candidate for a key role in effector T cell kinetics postCreperfusion, potentially influencing MVO. These findings identify a possible therapeutic target in I/R injury postCPPCI, opening up a new avenue for further research and future treatment development.