Circulation, Vol 90, 2390-2401, Copyright © 1994 by American Heart Association
DJ Lefer, DM Flynn, ML Phillips, M Ratcliffe and AJ Buda
BACKGROUND--Polymorphonuclear leukocytes (PMNs) have been shown to mediate
coronary vascular and myocardial tissue injury after coronary artery
ischemia and reperfusion. Previous studies using specific monoclonal
antibodies directed against P-selectin and L-selectin have demonstrated the
involvement of the selectin family of glycoproteins in the early phase of
PMN-induced myocardial ischemia-reperfusion injury. We examined the effects
of a novel oligosaccharide analog of sialyl LewisX (SLeX), which blocks
both P-selectin and E-selectin in an acute canine model of myocardial
ischemia and reperfusion. METHODS AND RESULTS--Anesthetized, open-chest
dogs were subjected to 1.5 hours of left circumflex coronary artery (LCx)
occlusion followed by 4.5 hours of reperfusion and randomly received the
SLeX analog CY-1503 (5 mg/kg IV), the nonfucosylated analog of CY-1503, SLN
(5 mg/kg IV), or saline 5 minutes before reperfusion. The investigators
were blinded to the treatment until all the data analysis was completed.
All three groups of dogs exhibited similar and severe reductions in
transmural myocardial blood flow in the LCx region as well as pronounced
myocardial contractile dysfunction during occlusion, suggesting comparable
degrees of myocardial ischemia. After reperfusion, dogs receiving saline (n
= 6) displayed an enhanced degree of myocardial injury that was evidenced
by a dramatic elevation in plasma creatine kinase (CK) activity, PMN
accumulation, and myocardial necrosis. Plasma CK activity increased from
1.9 +/- 0.5 IU/microgram protein at baseline to 73.0 +/- 11.0 IU/micrograms
protein (P < .001) at 4.5 hours of reperfusion and myocardial PMN
accumulation, as measured by cardiac myeloperoxidase (MPO) activity, and
was significantly enhanced (P < .01) within the necrotic zone compared
with the nonischemic zone (4.3 +/- 0.6 versus 0.7 +/- 0.1 U/100 mg tissue).
After 4.5 hours of reperfusion, 36% of the myocardium within the ischemic
zone and 17% of the left ventricle became necrotic in the dogs receiving
saline. Treatment with CY-1503 (n = 6) significantly (P < .05) blunted
plasma CK activity by more than 50% throughout the reperfusion period,
reduced necrotic zone PMN accumulation by 63% (P < .05), and reduced
myocardial necrosis in the area at risk by 65% (P < .01) and by 72%
within the left ventricle (P < .01). In contrast, administration of the
nonfucosylated analog of CY-1503, SLN (n = 6), failed to exert any
detectable cardioprotective effects after myocardial ischemia and
reperfusion. CONCLUSIONS--Our results provide strong evidence that
treatment with a unique carbohydrate analog of SLeX, CY-1503, significantly
reduces the degree of myocardial injury associated with coronary artery
ischemia and reperfusion. The profound cardioprotection appears to be
related to a reduction in PMN accumulation within the ischemic-reperfused
myocardium. Additional studies investigating more- prolonged periods of
reperfusion are required to determine whether CY- 1503 treatment merely
delays the onset or actually reduces the full extent of myocardial necrosis
after ischemia and reperfusion.
ARTICLES
A novel sialyl LewisX analog attenuates neutrophil accumulation and myocardial necrosis after ischemia and reperfusion
Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112.
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