‘Hot stuff': inflammatory lymphocyte populations in acute coronary syndrome

Acute myocardial infarction and coronary unstable plaque: definitely ‘hot stuff' to address. However, it is not just a pun. Atherosclerosis and acute coronary syndrome are both characterized by active inflammation.¹ Increased levels of C-reactive protein and inflammatory cytokines have been found during the very early phases of acute myocardial infarction² and are associated with a worse prognosis.¹

The immune system also participates in almost every phase of atherosclerotic disease.³ There is increasing evidence that both adaptive and innate immunity tightly regulate atherogenesis. Adaptive immune populations, particularly T cells, regulate the magnitude of the pro-inflammatory atherogenic response. Immune-mediated processes are involved during the onset, development and rupture of coronary plaques, where the presence of activated T lymphocytes was demonstrated decades ago.⁴ CD4⁺, and to a lesser extent CD8⁺ T cells, localize in atherosclerotic plaques. T cells also influence the stability of the atherosclerotic lesion and thus the propensity for thrombus formation and the clinical outcome of disease. T-cell responses observed in patients with unstable angina are antigen-driven and directed against antigens contained in coronary atherosclerotic plaques.⁵ Patients with unstable angina are characterized by a perturbation of the functional T-cell repertoire with a bias toward interferon-gamma production, suggesting that monocyte activation and acute phase responses are consequences of T-cell activation.⁶ Interferon-gamma is produced by CD4⁺CD28^null T cells, which are expanded in patients with unstable angina yet demonstrably low in patients with stable angina and controls. Several novel CD4⁺ T-cell subsets, including Th9 cells and Th17 cells, have recently been identified during the progression of coronary atherosclerosis.

Early atherosclerosis is particularly influenced by lymphocyte activity. When atherosclerosis-prone (LDLR^−/−) mice were crossed with lymphocyte-deficient (RAG1^−/−) mice to generate double knockout progeny, lesion development was reduced by 54% in double knockout mice compared with matched LDLR^−/− controls.⁷ Transfer of CD4⁺ T cells from apoE^−/− to immunodeficient apoE^−/−/scid/scid mice increased atherosclerotic lesions by 164%.⁸ This increase was associated with the infiltration of transferred T cells into lesions, thus indicating that CD4⁺ T cells promote disease during atherosclerosis.

Particular reservoirs of T cells seem to be associated with early aggressive forms of coronary atherosclerosis. In small studies, non-diabetic patients with early clinical presentation of coronary heart disease showed lower CD3⁺CD8⁺ levels, whereas their CD4⁺ populations were higher⁹. Additionally, CD8⁺ levels were inversely related to the severity of coronary atherosclerosis. CD4⁺CD28^null T cells were expanded in patients with unstable angina and infrequent in patients with stable angina.¹⁰ A patient's CD4⁺CD28^null T-cell frequency was shown to be an independent predictor of future acute coronary events.

However, we must acknowledge that are we are moving into very poorly charted territories. You, Yun and colleagues shed light on this topic with their recent paper. Interestingly, the frequency of CD57⁺ cells in the CD8⁺ T-cell population was found to correlate not only with cytokine activation but also with a ‘hard' clinical outcome such as cardiovascular mortality 6 months after acute myocardial infarction. The authors note that the expression of the CD57 epitope on T cells may be a surrogate marker of replicative senescence. Beyond any value in risk stratification of acute coronary syndrome, analysis of such a lymphocyte population offers a potential therapeutic strategy via modification of T-cell responses.

Indeed, many additional studies are needed before a clear and complete understanding of the inflammatory and lymphocyte connections implied in the progression of atherosclerosis and the clinical onset of acute coronary syndrome can be achieved. ‘Hot' topic, ‘hot' stuff, ‘cool' studies to be done.