Intravenous aspirin at reperfusion does not reduce infarct size in the dog with a residual critical stenosis.

Platelet-related events being associated with the increment of infarct size at reperfusion in the presence of a residual stenosis, we tested in dogs whether intravenous aspirin (ASA) could limit infarct size. The left anterior descending coronary artery was occluded for 90 min and reperfused for 6 h in the presence of a residual critical stenosis. Controls received saline, and treated groups were given 2, 6, or 12 mg/kg ASA, i.v., 5 min before reperfusion. Infarct size did not differ significantly between groups (control, 43.80+/-6.28%; ASA, 2 mg/kg: 41.07+/-7.78%; ASA, 6 mg/kg: 37.55+/-3.44%; ASA, 12 mg/kg: 29.40+/-5.41%), as well as transmural collateral blood flow and [111In]-platelet accumulation in the infarcted myocardium (2.5-3.6 x 10(5) platelets/g). However, myocardial neutrophil accumulation was significantly reduced (p < 0.05) in groups given 6 (15.0+/-2.6 x 10(6)/g tissue) and 12 mg/kg (18.4 +/-3.8) ASA, but not in the 2-mg/kg group (21.0+/-5.2), as compared with control group (32.0+/-7.2). Ex vivo platelet aggregation to collagen was abolished during reperfusion in all treated groups (p < 0.05). Transcardiac arteriovenous differences in 6-keto-PGF1alpha were reduced significantly 1 h after reperfusion in groups given 6 or 12 mg/kg ASA (94.7+/-13.1 and 71.7+/-19.2 pg/ml, respectively) but not in the 2-mg/kg group (178.3+/-78.2 pg/ml), as compared with control (405.4+/-171.6 pg/ml). ASA-insensitive platelet activation at the site of stenosis or inhibition by ASA of prostacyclin production by jeopardized myocardium may explain the observed lack of benefit of ASA.

The low molecular weight heparin, enoxaparin, limits infarct size at reperfusion in the dog.

OBJECTIVE: Heparin (HEP) is used in the post-thrombolytic state to prevent vessel reocclusion, thereby aiding myocardial salvage. Side effects limit its benefits, but besides anticoagulant activity HEP has diffuse actions that may be potentially beneficial to jeopardized reperfused myocardium. This study compares the effect of therapeutic doses of HEP and enoxaparin (ENOX), a low molecular weight heparin, and to streptokinase (SK), on infarct size. METHODS: The left anterior descending coronary artery was occluded in dogs for 90 min, followed by 6 h of reperfusion with a residual critical stenosis in place. Five min before reperfusion, HEP (2800 IU) was injected i.v., and perfused at 500 IU/h until sacrifice in group 2, while groups 3 and 4 received ENOX (2128 anti-Xa IU i.v.) followed by 380 anti-Xa IU/h. Group 4 was also given 500,000 IU SK over 30 min before reperfusion beginning at 55 min of occlusion (ENOX + SK), while group 5 received only SK. Controls (CON, group 1) received saline. P-selectin mediated platelet-neutrophil rosettes formation was also tested in vitro in the presence of HEP and ENOX. RESULTS: The area at risk delimited by dye perfusion was statistically similar among groups. Covariance analysis between infarct size (% of area at risk) delimited with triphenyltetrazolium and collateral flow measured with radioactive microspheres confirmed that groups given ENOX (21.6 +/- 5.5%) and ENOX + SK (24.9 +/- 3.9%) developed smaller infarcts (P < 0.05) than CON (48.1 +/- 4.5%), as opposed to HEP (32.2 +/- 3.6%) and SK (46.8 +/- 3.4%) groups. 111In-platelet counts in the infarct were reduced significantly by 64% in the ENOX group as compared to CON, and to a lesser extent (42%, n.s.) in the ENOX + SK group, but were not reduced by HEP and SK treatments. Neutrophil accumulation in the infarcts was decreased significantly and by more than 75% in the ENOX and ENOX + SK groups versus CON, but not in the HEP and SK groups. Also, only ENOX (10-100 micrograms/ml) significantly inhibited platelet-neutrophil rosettes formation in a plasmatic milieu. CONCLUSIONS: The ENOX treatment, as opposed to that of HEP, reduces myocardial platelet and neutrophil accumulations, and limits infarct size when given just before and during reperfusion. The benefits of ENOX on infarct size were not modified by SK, and may be related, at least in part, to an interaction with P-selectin-mediated cell adhesion.

Cardioprotective effects of diltiazem during acute rejection on heterotopic heart transplants.

In the presence of severe rejection, cardiac allograft perfusion has been shown to be impaired. Since a functionally reversible vasoconstrictor component has been identified in this condition and rejection does not reverse if ischemia does not, we hypothesized that diltiazem may be beneficial in this condition. Experiments were performed on dogs with heterotopic heart transplants and chronic instrumentation for the assessment of allograft perfusion. Two groups of cardiac allograft recipients were studied: untreated recipients and recipients treated with the calcium antagonist diltiazem (180 mg twice daily, orally). Allograft blood flow was monitored daily along with plasma diltiazem levels. The lymphoproliferative response to mitogens was studied at selected intervals until terminal rejection. Contractile function of the graft was assessed daily by palpation. Without immunosuppression, terminal rejection was observed within 7 days. Rejection was confirmed by histology; cellular infiltration and myocyte necrosis were present in all cardiac allografts but to a significantly lesser degree in diltiazem-treated recipients. The mean blood flow of heterotopically implanted hearts was in the range of 35-50 ml/min, which decreased steadily in untreated recipients. In contrast, significant improvement of allograft perfusion was observed in diltiazem-treated recipients at days 4-6 after transplantation. Diltiazem also significantly attenuated mitogen-induced lymphocyte proliferation at peak sensitivity (2 days after transplantation). Diltiazem plasma concentrations were in the therapeutic range (30-60 ng/ml) before and after cardiac transplantation. Results of the present study demonstrate beneficial effects of diltiazem in the course of severe cardiac rejection. Such findings support its use during rejection when maintenance of graft blood flow and myocyte protection may be important for myocardial function and viability.

Importance of platelets in myocardial injury after reperfusion in the presence of residual coronary stenosis in dogs.

Residual coronary stenosis is common after successful thrombolysis for acute infarction. We investigated the role of platelets and the influence of a residual critical stenosis during early reperfusion in survival of reperfused myocardium. The left anterior descending coronary artery was occluded for 90 minutes and reperfused for 6 hours in 5 groups of dogs, 3 with a residual critical stenosis (groups 1 through 3) and 2 without (groups 4 and 5). Thrombocytopenia was produced by an antiserum in groups 2, 3, and 5; group 3 was also made neutropenic by another antiserum. Platelets (groups 1 and 4) and neutrophils (groups 1, 2, 4, and 5) labeled with indium 111 were reinjected at occlusion. Collateral flow was estimated with radioactive microspheres and was statistically similar among groups. Infarct size (percentage of area at risk), revealed by triphenyltetrazolium, was more severe (49.4% +/- 4.0%; p < 0.05) with stenosis (group 1) than without stenosis (group 4: 29.5% +/- 4.6%). Platelet depletion reduced infarct size in group 2 (28.6% +/- 6.3%; p < 0.05 vs group 1) with stenosis, but not in group 5 without stenosis (24.5% +/- 6.2% vs group 4: 29.5% +/- 4.6%). Neutropenia (group 3) did not decrease infarct size in thrombocytopenic dogs. Neutrophil accumulations in reperfused myocardium were similar among groups, but platelets accumulated in greater numbers in reperfused infarcts with stenosis (group 1: 338,581 +/- 52,857/gm; p < 0.05) than without stenosis (group 4: 153,445 +/- 23,949/gm). Therefore a critical stenosis at reperfusion compromises myocardial salvage and increases infarct size by means of a platelet-mediated mechanism.