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Circulation, Vol 88, 673-683, Copyright © 1993 by American Heart Association
M Galinanes, CS Lawson, R Ferrari, GA Limb, NW Derias and DJ Hearse
BACKGROUND. Since there is considerable evidence that leukocytes contribute
to tissue injury during ischemia and reperfusion, the present study was
designed to: (1) determine whether reperfusion in vivo with leukopenic
blood affords protection in a model of reversible hypothermic ischemia, (2)
determine the duration of any protection, (3) characterize the relation
between protection and duration of leukopenic perfusion, and (4) assess the
effect of leukopenic reperfusion on myocardial glutathione content. METHODS
AND RESULTS. Rat hearts (n = 12 per group) were excised, immediately
arrested with an infusion (2 minutes at 4 degrees C) of St Thomas'
cardioplegic solution, and subjected to 4 hours of global ischemia (4
degrees C). The hearts were then transplanted (1 hour additional ischemic
time) into the abdomen of saline-treated or leukopenic recipients.
Leukopenia was induced by intraperitoneal administration of mustine
hydrochloride (2 mg/kg) 3 days before study. Hearts were then reperfused in
situ for 1, 4, or 24 hours, after which they were excised and either
processed for histological examination (n = 4 per group) or perfused
aerobically with bicarbonate buffer for 20 minutes, and contractile
function was assessed (n = 8 per group); at the end of this period, some
hearts (n = 5 per group) were taken for metabolite analysis. After 1 hour
of reperfusion, contractile function in the saline-treated control group
was significantly reduced compared with aerobic controls that had not been
subjected to ischemia (left ventricular developed pressure [LVDP], 108 +/-
5 vs 126 +/- 3 mm Hg at an end-diastolic pressure of 12 mm Hg; P < .05).
However, in the hearts with leukopenic reperfusion, LVDP (119 +/- 2 mm Hg)
was similar to that of aerobic controls. This benefit, however, was lost
after 4 and 24 hours of reperfusion. Cardiac compliance was not influenced
by leukopenia. Coronary flow recovered significantly better in the
leukopenic hearts during the first 4 hours of reperfusion (11.8 +/- 0.5 vs
9.3 +/- 0.4 mL/min at 1 hour and 10.0 +/- 0.5 vs 8.0 +/- 0.4 mL/min at 4
hours, P < .05), but again this benefit was lost after 24 hours of
reperfusion. The myocardial contents of reduced and oxidized glutathione
after 1, 4, and 24 hours of reperfusion were similar in saline-treated and
leukocyte-depleted animals. In additional studies, the period of ischemia
was extended to 8 hours, and similar results were obtained, with improved
recovery of contractile function and coronary flow but not cardiac
compliance in the leukopenic group after 1 hour of reperfusion. In further
studies with the isolated blood-perfused rat heart, ischemia was induced
for 8 hours; this was followed first by reperfusion for 0, 2, 10, 30, or 60
minutes with leukopenic blood and then by perfusion with blood from
saline-treated animals for 60, 58, 50, 30, or 0 minutes, respectively.
Reperfusion with leukopenic blood for 2 minutes did not improve the
recovery of LVDP (106 +/- 7 vs 96 +/- 10 mm Hg in controls; NS) but when
continued for 10, 30, or 60 minutes resulted in significant improvements
(137 +/- 5, 138 +/- 3, and 150 +/- 10 mm Hg, respectively). Although
coronary flow tended to be greater in all leukopenic groups, by the end of
60 minutes of reperfusion, only those hearts reperfused with leukopenic
blood for the entire reperfusion period showed a significant improvement
(3.4 +/- 0.3 vs 2.5 +/- 0.2 mL/min in controls; P < .05). Histological
studies revealed no intravascular aggregation of leukocytes or features of
myocyte necrosis. CONCLUSIONS. Reperfusion with leukopenic blood
accelerated the rate of recovery of cardiac function after reversible
myocardial injury but did not lead to a sustained increase in the eventual
extent of recovery. Reperfusion with leukopenic blood for the first 10
minutes of reflow is sufficient to obtain this benefit.
ARTICLES
Early and late effects of leukopenic reperfusion on the recovery of cardiac contractile function. Studies in the transplanted and isolated blood-perfused rat heart
Cardiovascular Research, Rayne Institute, St Thomas' Hospital, London, UK.
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