Effects of a Monoclonal Antibody to P-Selectin on Recovery of Neonatal Lamb Hearts After Cold Cardioplegic Ischemia

Nagashima, Mitsugi MD
Shin'oka, Toshiharu MD
Nollert, Georg MD
Shum-Tim, Dominique MD
Hickey, Paul R. MD
Roth, Stephen J. MD
Kirchhoff, Antje MD
Springer, Timothy A. PhD
Burke, Philip R. BS
Mayer, John E. Jr, MD

From the Departments of Cardiovascular Surgery (M.N., T.S., G.N., D.S.-T., J.E.M.), Anesthesia (P.R.H.), and Cardiology (S.J.R.), Children's Hospital and Harvard Medical School; and the Department of Pathology and Center for Blood Research (A.K., T.A.S., P.R.B.), Harvard Medical School, Boston, Mass.
Reprint requests to John E. Mayer Jr, MD, Department of Cardiovascular Surgery, Children's Hospital, 300 Longwood Ave, Boston, MA 02115.

Circulation 98(19S):p 391II-397II, November 10, 1998.

Background

The interaction between endothelium and leukocytes plays a crucial role in ischemia-reperfusion injury. P-selectin, which is expressed on activated endothelium, mediates the first step in leukocyte adherence to the endothelium. This study examined the effects of a monoclonal antibody (mAb) against P-selectin on the recovery of cardiac function and myocardial neutrophil infiltration after ischemia.

Methods and Results-Thirteen blood-perfused, isolated neonatal lamb hearts underwent 2 hours of hypothermic cardioplegic arrest and 2 hours of reperfusion. Immediately before reperfusion, mAb to P-selectin was administered to the perfusate (15 [micro sign]g/mL) in 6 hearts (group P-sel). In control (n=7), the same volume of saline was added. Isovolumic left ventricular function and coronary blood flow were measured. At 2 hours after reperfusion, myocardial myeloperoxidase activity, an index of neutrophil accumulation, was assayed. At 30 minutes of reperfusion, hearts treated with mAb to P-selectin achieved significantly greater recovery of maximum developed pressure (70 +/- 4% in control versus 77 +/- 2% in group P-sel, P<0.01), maximum positive first derivative of pressure (dP/dt) (64 +/- 7% in control versus 73 +/- 5% in group P-sel, P<0.05), and maximum negative dP/dt (61 +/- 6% in control versus 70 +/- 6% in group P-sel, P<0.05) compared with control. Percent baseline of coronary blood flow was also significantly increased in group P-sel (135 +/- 40% in control versus 205 +/- 43% in group P-sel, P<0.05). Myocardial myeloperoxidase activity was significantly lower (P<0.05) in group P-sel (4.7 +/- 3.2) versus control (16.0 +/- 10.1). (Units are change in absorbance/min/g tissue.)

Conclusions

The functional blockade of P-selectin resulted in better recovery of cardiac function and attenuated neutrophil accumulation during early reperfusion. Strategies to block P-selectin mediated neutrophil adherence may have clinical application in improving myocardial function at early reperfusion. (Circulation. 1998;98:II-391-II-398.)