Reduction of canine infarct size by bolus intravenous administration of liposomal prostaglandin E1: comparison with control, placebo liposomes, and continuous intravenous infusion of prostaglandin E1.

Prostaglandin E1 (PGE1) reduces experimental infarct size when administered by prolonged low-dose left atrial infusion during coronary occlusion. Liposomal delivery of PGE1 may enhance biologic activity and limit adverse hemodynamic effects. The purpose of this study was to test the hypothesis that intravenous bolus administration of liposomal PGE1 (TLC C-53, The Liposome Company, Princeton, N.J.) during coronary occlusion would result in myocardial salvage. We compared TLC C-53 (0.5 microgram/kg intravenous bolus at 10 and 100 min of occlusion of the left anterior descending coronary artery [LAD]), free PGE1 (0.1 microgram/kg/min infused 10 min after LAD occlusion until reperfusion), placebo liposomes, and control (n = 7 for each group) in an open-chest canine model of 2 hours of LAD occlusion and reperfusion. Infarct size as a percentage of risk area (mean +/- SD) in the control group (58.4% +/- 20.0%) was similar to that in animals given placebo liposomes (53.1% +/- 12.6%) but was significantly reduced in the groups given TLC C-53 (33.5% +/- 9.2%; p < 0.01) or free PGE1 (37.2% +/- 4.8%; p < 0.05) groups. Infarct salvage was significant (p < 0.05) for the TLC C-53-and PGE1-treated dogs compared with the control dogs, independent of collateral blood flow by analysis of covariance. Moreover, the ischemic-zone blood flow during reperfusion was significantly higher in the TLC C-53 group compared with the control group or the group receiving free PGE1. Neutrophil infiltration of ischemic myocardium was significantly inhibited by TLC C-53 as determined by myeloperoxidase assay. Unlike free PGE1, TLC C-53 did not cause significant tachycardia or hypotension during therapy. In conclusion, TLC C-53 administered intravenously during coronary occlusion significantly reduced infarct size, limited neutrophil infiltration, and improved myocardial blood flow during reperfusion without adverse hemodynamic consequences.

Infarct salvage with liposomal prostaglandin E1 administered by intravenous bolus immediately before reperfusion in a canine infarction-reperfusion model.

BACKGROUND: Prostaglandin E1 (PGE1) inhibits leukocyte and platelet function and reduces infarct size during left atrial infusion. Intravenous liposomal PGE1 (TLC C-53) accelerates thrombolysis and prevents reocclusion in canine coronary thrombosis. We tested the hypothesis that intravenous TLC C-53 would attenuate reperfusion injury in a canine infarction-reperfusion model. METHODS AND RESULTS: Twenty-one open-chest dogs were randomized to receive a 10-minute intravenous infusion of either liposome diluent (placebo), free PGE1 (2 micrograms/kg), or TLC C-53 (2 micrograms/kg PGE1) after 2 hours of left anterior descending (LAD) occlusion just before reperfusion. Hemodynamic assessment, regional myocardial blood flow determination with radioactive microspheres, myocardial leukocyte infiltration by myeloperoxidase assay, and estimation of infarct size using triphenyl tetrazolium chloride staining were performed. Regional fractional shortening was measured with sonomicrometer crystals implanted in the midmyocardium. Infarct size as a percentage of the risk region was significantly reduced (P < .05) with TLC C-53 (37.9 +/- 17.4%) compared with PGE1 (56.7 +/- 13.9%) or placebo (58.0 +/- 9.9%) infusion. Infarct salvage with TLC C-53 was independent of collateral blood flow by ANCOVA. There was a dramatic reduction in myeloperoxidase activity in the infarct, risk, and border regions of dogs treated with TLC C-53 compared with placebo. Enzyme activity was also significantly reduced (P < .05) in the infarct zone with TLC C-53 (0.11 +/- 0.1 U/100 mg) treatment compared with PGE1 (0.38 +/- 0.3 U/100 mg). No significant differences in regional myocardial blood flow or myocardial function among treatment groups were identified, although there was a trend toward improved function in the TLC C-53 dogs. CONCLUSIONS: Bolus intravenous administration of TLC C-53 immediately before reperfusion results in reduced leukocyte infiltration and substantial infarct salvage. TLC C-53 mah be useful in limiting reperfusion injury during treatment of acute myocardial infarction.

Enhanced thrombolysis, reduced coronary reocclusion and limitation of infarct size with liposomal prostaglandin E1 in a canine thrombolysis model.

OBJECTIVES: The purpose of this study was to test the hypothesis that liposomal prostaglandin E1 (TLC C-53) would result in more rapid thrombolysis, less reocclusion and smaller infarct size when administered with heparin and streptokinase in a canine thrombolysis model. BACKGROUND: In experimental animals, prostaglandin E1 has been shown to augment thrombolysis, improve coronary flow and reduce infarct size when infused directly into the left atrium. TLC C-53 is a stable preparation of prostaglandin E1 bound by phospholipid microspheres that produces fewer adverse hemodynamic effects during intravenous use. METHODS: To investigate the effects of TLC C-53 on coronary patency and infarct salvage, we studied 30 conditioned open chest dogs. After coil-induced left anterior descending coronary artery occlusion and 1 h of clot maturation, the dogs were randomly assigned to receive a 10-min intravenous infusion of either TLC C-53 (2 micrograms/kg body weight) or placebo. Both groups then received intravenous heparin and streptokinase. Hemodynamic variables and Doppler coronary flow were monitored, and myocardial blood flow was determined using radioactive microspheres. Infarct size was assessed with triphenyltetrazolium chloride staining. RESULTS: Thrombolysis time was accelerated from 79 +/- 38 to 47 +/- 9 min (mean +/- SD), and coronary patency was greater (100% vs. 50%) with TLC C-53 than with placebo (p < 0.05). Moreover, for arteries that recanalized, coronary Doppler flow and myocardial perfusion were more severely impaired with placebo. Infarct size as a percent of the area at risk was higher (p < 0.05) with placebo (51 +/- 15%) than with TLC C-53 (33 +/- 14%). Neutrophil infiltration into ischemic myocardium determined by myeloperoxidase assay was also significantly greater in the placebo group. CONCLUSIONS: TLC C-53 administered intravenously before thrombolytic therapy resulted in a significant acceleration of thrombolysis time, improvement in coronary patency and blood flow during reperfusion and a reduction in infarct size.

Differential effects of synchronized coronary sinus retroperfusion on regional myocardial function during brief occlusion of the left anterior descending and circumflex coronary arteries.

To test the hypothesis that coronary sinus retroperfusion would preserve regional myocardial function during either left anterior descending or circumflex occlusion, sonomicrometer crystals were implanted in the midmyocardium of five chronically instrumented dogs. Regional fractional shortening was measured during 5 min of coronary occlusion with and without retroperfusion. Percent fractional shortening in the left anterior descending region fell from 18% at baseline to -4%(dyskinesis) after 3 min of left anterior descending occlusion. With coronary sinus retroperfusion, the percent fractional shortening declined from 16% at baseline to 0 (akinesis) during occlusion. A modest but significant improvement in percent fractional shortening in the ischemic region during left anterior descending occlusion occurred with retroperfusion (p < .05). By contrast, no amelioration of ischemic dysfunction occurred with retroperfusion during circumflex occlusion. Coaxial flow into the great cardiac vein during retroperfusion may provide preferential protection to ischemic myocardium supplied by the left anterior descending coronary artery. However, it is unlikely that the modest degree of improvement in regional function observed during acute left anterior descending occlusion would be mechanically important in the presence of significant ischemic dysfunction.

Improved regional myocardial blood flow, left ventricular unloading, and infarct salvage using an axial-flow, transvalvular left ventricular assist device. A comparison with intra-aortic balloon counterpulsation and reperfusion alone in a canine infarction model.

BACKGROUND: It has been suggested that left ventricular unloading at the time of reperfusion provides superior infarct salvage over reperfusion alone. The purpose of this study was to show that the Hemopump transvalvular axial-flow left ventricular assist device provides superior left ventricular unloading, ischemic zone collateral blood flow, and infarct size reduction compared with intra-aortic balloon counterpulsation and reperfusion alone. METHODS AND RESULTS: Eighteen dogs were instrumented with regional myocardial function sonomicrometers in the ischemic and control zones. The left anterior descending coronary artery just distal to the first diagonal branch was instrumented with a silk snare and Doppler flow probe. Additionally, pressure catheters were placed in the left atrial appendage, left ventricular apex, and ascending aorta for hemodynamic measurements. Regional myocardial blood flow was determined by using 15-microns radioactive microspheres. Measurements were made in the control state, immediately after coronary occlusion, at 1 and 2 hours after coronary occlusion, with reperfusion, and 1 hour after reperfusion. In treated animals, left ventricular assistance was maintained during the entire period of occlusion and reperfusion. The Hemopump was associated with a significant decrease in left ventricular systolic and diastolic pressure, whereas mean arterial pressure was maintained. Intra-aortic balloon counterpulsation resulted in no significant changes in left ventricular systolic pressure and a modest decrease in left ventricular diastolic pressure. Regional unloading as assessed by sonomicrometers was significant in the Hemopump animals and absent in the balloon pump animals. Absolute regional myocardial blood flow in the ischemic zone increased slightly (p = 0.002) in the Hemopump animals and did not change in the balloon pump animals. Infarct size expressed as percentage of the zone at risk was 62.6% in the control animals, 27.22% in the balloon pump animals, and 21.7% in the Hemopump animals. CONCLUSIONS: Mechanical unloading of the ventricle during ischemia and reperfusion appears to result in significant infarct salvage compared with reperfusion alone. The Hemopump appears to provide superior left ventricular systolic and diastolic unloading compared with intra-aortic counterpulsation in a canine model.

Neonatal and maternal hair zinc levels in a nonhuman primate model of the fetal alcohol syndrome.

The role of zinc deficiency in the etiology of ethanol-associated fetotoxicity was assessed by measurement of maternal and newborn hair zinc content in a nonhuman primate model of the fetal alcohol syndrome. The model best approximates the human situation for length of gestation and type of placentation, coupled with the ability to control for nutritional factors. All mothers received 110% of their minimum daily caloric requirements as a balanced, nutritionally complete diet, including a minimum of 3.5 mg zinc per day. Over a 2-year period, maternal hair samples from 17 pregnancies (using 12 females) were obtained at term. There were 16 live, full-term neonates (nine ethanol exposed and seven control) from whom samples were taken within 1 hr of birth. The ethanol-exposed infant monkeys had a significantly higher incidence of craniofacial dysmorphology and developmental delay compared to the controls. There was no difference in hair zinc levels between ethanol-exposed and control animals for either the mothers or the newborns. Neonatal levels were, however, consistently higher than corresponding maternal. Although the findings cannot exclude transient or early gestational zinc deficiency as a factor, they provide further evidence that ethanol (and/or its metabolites) is the proximate toxin in the type of fetal injury seen in the fetal alcohol syndrome.