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Altered CD18 leucocyte integrin expression and adhesive function in patients with an acute coronary syndrome
  1. GRAHAM S HILLIS,
  2. WILLIAM C DALSEY,
  3. CAROL A TERREGINO*,
  4. IERACHMIEL DASKAL,
  5. ANTOINETTE NANGIONE
  1. Departments of Emergency Medicine and Laboratory Medicine
  2. Albert Einstein Medical Center
  3. Philadelphia, Pennsylvania, USA
  4. *Department of Emergency Medicine
  5. Cooper Hospital/University Medical Center
  6. Camden, New Jersey, USA
  1. Dr Graham Hillis, Department of Cardiology, The Royal Infirmary, Lauriston Place, Edinburgh, EH3 9YW, UK grahamhillis{at}hotmail.com

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The adhesion of leucocytes to vascular endothelium is fundamental to the pathogenesis of atherosclerosis and the acute coronary syndromes. The CD11b/CD18 receptor is particularly important in this process. This molecule is expressed on both neutrophils and monocytes. In common with other integrin receptors it consists of α and β subunits (CD11b and CD18, respectively), which allow binding of leucocytes to the endothelial surface.1

The aims of our study were: (1) to compare the expression of CD11b and CD18 on peripheral neutrophils and monocytes in patients with an acute coronary syndrome, patients with stable coronary artery disease, and healthy controls; and (2) to assess any functional change in neutrophil adhesion in the acute coronary syndrome.

Twenty two consecutive patients with an acute coronary syndrome were studied. None had received thrombolytics or glycoprotein IIb/IIIa inhibitors and none had undergone coronary revascularisation. All were on maintenance aspirin (n = 19) or had received > 12 hours of such treatment in hospital (n = 3). Twelve patients with stable coronary artery disease were also studied. All had a > 50% stenosis of at least one major coronary artery, had stable cardiac symptoms over the past six months, and were taking maintenance aspirin. The third group consisted of 12 healthy volunteers with no cardiac history or symptoms. These subjects were asked to take aspirin for three days before blood sampling. None of the patients or volunteers studied had conditions known to affect leucocyte adhesion molecule expression or function.

Cell surface expression of the CD11b and CD18 subunits was determined by flow cytometry. Functional changes in neutrophil adherence were assessed using a well validated technique that relies on their ability to adhere to nylon columns.2 The assay determines percentage neutrophil adherence, with 98% of this adhesion mediated by CD18.2 In our laboratory it has a coefficient of variation of 5.4%.

Results are presented as mean (SE) unless otherwise stated. Kruskal-Wallis and Mann-Whitney U tests were used to compare groups, with a double sided p value < 0.05 considered significant.

Among the 22 patients with an acute coronary syndrome the mean duration of symptoms before blood sampling was 15.4 (2.2, range 1–36) hours. Fourteen patients were ultimately diagnosed as having unstable angina, five had a non-Q wave myocardial infarction, and three sustained a Q wave myocardial infarction.

Expression of CD11b and CD18 was similar on neutrophils and monocytes from patients with stable coronary artery disease and healthy controls (table 1). However, monocytes from patients with an acute coronary syndrome had higher expression of CD11b and CD18. Neutrophil CD18 expression was also higher in unstable patients, when compared with healthy controls, though not those with stable coronary artery disease (table 1). There was no difference in CD18 mediated neutrophil adhesion in healthy subjects and patients with stable coronary artery disease (table 1). In contrast, CD18 mediated neutrophil adhesion was lower among patients with an acute coronary syndrome than either of these control populations. Neutrophil adhesion was lowest among patients with an acute coronary syndrome who had evidence of myocardial damage at the time of blood sampling (concurrent cTnI concentrations > 0.1 ng/ml). Conversely, the expression of CD11b and CD18 was highest among patients with positive cTnI. The numbers in these subgroups are, however, small.

Table 1

CD18 and CD11b expression on leucocytes plus percentage neutrophil adhesion in patients with an acute coronary syndrome (with and without concurrent cardiac troponin I concentrations > 0.1 ng/ml), patients with stable coronary artery disease, and healthy controls

Patients with an acute coronary syndrome in whom cTnI is negative lie between those with stable symptoms (who have lower CD11b and CD18 expression but greater CD18 mediated neutrophil adhesion) and patients with positive cTnI (who have higher cell surface expression of CD11b and CD18 but reduced function). This trend is particularly pronounced in the case of CD11b expression by monocytes (p < 0.01), and to a lesser extent for CD18 mediated neutrophil adhesion (p = 0.06) and expression of this molecule by monocytes (p = 0.07).

This small study provides further evidence that unstable coronary artery disease is associated with an inflammatory response. In particular, it demonstrates changes in peripheral leucocyte adhesion molecule expression and, perhaps more importantly, function among patients with an acute coronary syndrome. The principal differences are in the expression of the CD11b and CD18 on monocytes. Both of these molecules are more strongly expressed among patients with unstable disease. Neutrophils from patients with acute coronary syndrome also express more CD18 than those from healthy controls. Despite this, CD18 mediated neutrophil adherence is lowest among patients with an acute coronary syndrome. The increases in monocyte CD11b/CD18 expression and reductions in neutrophil CD18 function are most pronounced in patients with concurrent evidence of myocardial necrosis, though less prominent changes are also evident in patients without evidence of cardiac damage.

Increased expression of CD11b/CD18 is found on neutrophils and monocytes sampled from the coronary sinus blood of patients with unstable angina and in peripheral blood following acute myocardial infarction.3 4 It has been suggested that these latter increases are related to myocardial necrosis.4 While this may accentuate leucocyte activation, the current data suggest that particularly monocyte induction is apparent even in the absence of cardiac damage. Activation of monocytes may result in increased adherence to endothelial surfaces and transmigration into the subendothelium, where they can further destabilise atherosclerotic plaques. Monocyte infiltration may also cause increased concentrations of tissue factor, enhancing the risk of thrombotic vessel occlusion and local vasoconstriction.

Intuitively, the reduction in CD18 mediated neutrophil adhesion in patients with an acute coronary syndrome is unexpected, particularly when increased cell surface expression of CD18 is apparent. Similar reductions in neutrophil adherence have, however, been demonstrated in acute sepsis, and increased CD18 integrin expression is not always associated with altered function. Perhaps the most likely explanation is that increases in CD18 mediated adhesion are transient. Certainly, this appears to be the case in vitro, where phorbol esters induce a 10-fold increase in CD11b/CD18 adherence within 15 minutes, falling to below normal within an hour.5 This is associated with a much smaller increase in cell surface CD11b/CD18 expression (2–3 times) which continues to rise steadily beyond this time point.5

In addition to the small sample size, the current study has several limitations. Aspirin reduces the adherence of neutrophils and lymphocytes, and we therefore controlled for such treatment. It is, however, uncertain what influence other agents might have on CD18 expression and function. Similarly, patients with an acute coronary syndrome had a higher prevalence of cardiovascular risk factors and this could represent an alternative explanation for our findings.

In conclusion, the current study reports increased CD11b/CD18 expression on leucocytes from patients with an acute coronary syndrome. This is associated with reduced CD18 mediated neutrophil adhesion in vitro. Further work is required to clarify the reasons for this paradox and to assess whether the observed changes in leucocyte CD18 biology represent a cause or an effect of the acute event.

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