The adhesion molecule P-selectin and cardiovascular disease – cardiac surgical implications

T.W Koh*, A.C DeSouza and J.R Pepper

Department of Cardiology and Cardiac Surgery, Barts and the London NHS Trust, London Chest Hospital, Bonner Road London E2 9JX, UK
Department of Cardiac Surgery, Royal Brompton and Harefield NHS Trust, London, UK

* Corresponding author. Tel: +44-208-983-2457, Fax: +44-208-983-2278
E-mail address: tatkoh{at}hotmail.com

We have read with interest the timely review by Blann et al.1 (December issue) on the adhesion molecule P-selectin and cardiovascular disease. This is a very comprehensive review on the subject and we would like to commend the authors. We would, however, like to highlight work (including our own) on P-selectin in the cardiac surgery setting, which the article does not cover.

The relatively recent availability of sensitive and specific markers of myocardial injury such as troponin has led to the observation that myocardial injury occurs even after apparently uncomplicated cardiac surgery. Despite employing myocardial preservation methods, myocardial ischaemia and reperfusion are unavoidable consequences of cardiac surgery. Leukocyte-endothelial interactions mediated by cell adhesion molecules including P-selectin may well be one such mechanism by which this myocardial injury occurs. Indeed, as Blann and colleagues point out, monoclonal antibodies designed to block these interactions between P-selectin, endothelium and leucocytes, have been shown to ameliorate myocardial ischaemia-reperfusion injury in animal models.

Boldt et al.2 showed elegantly that only patients undergoing cardiac surgery (with cardiopulmonary bypass), and not those having major abdominal or lung surgery, showed elevation of P-selectin and other soluble cell adhesion molecules (ICAM-1 and VCAM-1) 2 and 5 h after cardiac surgery. It was therefore postulated that activation of pro-inflammatory cascades, ischaemia and reperfusion phenomenon, and microcirculatory dysfunction may be the mechanisms for this difference and could be the target of modulation.

These observations were also confirmed in children and infants undergoing surgery with cardiopulmonary bypass by Blume et al.3 P-selectin (and E and L selectin as well) rose in the 6 h after cardiopulmonary bypass. Peak soluble P-selectin levels were also found to be associated with total cardiopulmonary support time and preoperative cyanosis. Thus, soluble adhesion molecule levels after cardiopulmonary bypass change most significantly in patients with the highest potential for vascular injury such as those with longer pump times and in cyanotic patients.

The institution of an artificial non-pulsatile circulation, namely, cardiopulmonary bypass itself, has a detrimental effect by inducing a systemic inflammatory response – so-called "post perfusion syndrome". We concur with Blann and colleagues that the observation of elevation in soluble P-selectin may not, per se, be a reflection of a response to inflammatory cytokines.

We have been able to show that in patients not subjected to cardiopulmonary bypass, during beating heart (off-pump) surgery using the "Octopus" device, that soluble P-selectin levels become elevated in coronary sinus blood draining directly from the heart within 5 min of reperfusion.4 In addition, P-selectin levels were significantly correlated with troponin I, a sensitive marker of myocardial injury. Others have also observed similar changes in soluble adhesion molecules, including P-selectin, in cardiac surgery patients not subjected to cardiopulmonary bypass. Thus, elevation of P-selectin can be a direct consequence of coronary occlusion (in our study, for mean of 17 min) during beating heart surgery, and can be independent of the pro-inflammatory effect of cardiopulmonary bypass.

Finally, recent work on saphenous vein grafts by Chello et al.5 show upregulation of P-selectin on saphenous vein endothelium when subjected to mechanical trauma in the form of pressure distension. They demonstrated greater adhesion of both unstimulated and activated neutrophils in distended veins compared with control veins. It has been postulated that neutrophil-endothelial interaction may be involved in the pathogenesis of early graft occlusion.

Thus, leukocyte-endothelial interactions mediated by cell adhesion molecules, in particular P-selectin, are likely to be important in the cardiac surgical field, one in which amelioration of myocardial ischaemia and reperfusion injury and graft failure remain challenges to the cardiac surgeon. This field remains an area of fruitful, on-going clinical and basic research for mechanisms to modulate such interactions to produce clinical benefit to the cardiac surgical patient.

References

  1. Blann AD, Nadar SK, Lip GY et al. The adhesion molecule P-selectin and cardiovascular disease. Eur. Heart J. 2003;24:2166–2179.[Abstract/Free Full Text]
  2. Boldt J, Kumle B, Papsdorf M et al. Are circulating adhesion molecules specifically changed in cardiac surgical patients. Ann. Thorac. Surg. 1998;65:608–614.[Abstract/Free Full Text]
  3. Blume ED, Nelson DP, Gauvreau K et al. Soluble adhesion molecules in infants and children undergoing cardiopulmonary bypass. Circulation. 1997;96:II-352–II-357.
  4. Koh TW, Davidson S, Pepper JR et al. Myocardial release of P-selectin following ischemia during beating heart coronary artery bypass surgery. J. Am. Coll. Cardiol. 2001;37:309A.
  5. Chello M, Mastroroberto P, Frati G et al. Pressure distension stimulates the expression of endothelial adhesion molecules in the human saphenous vein graft. Ann. Thorac. Surg. 2003;76:453–458.[Abstract/Free Full Text]




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