Activated protein C has a protective effect against myocardial I/R injury by improvement of endothelial function and activation of AKT1.

OBJECTIVES: Activated protein C (APC) has a protective efficacy against ischemia-reperfusion (I/R) injury in several organs. The objective of this study was to investigate effect of APC in myocardium with possible mechanism. METHODS: We used regional and global myocardial I/R injury models of rats. They consisted of I/R injuries (1) by ligation of left coronary artery, or (2) using Langendorff apparatus. Langendorff was used to focus the mechanism of APC excluding coagulation cascade in a working heart. Each experiment had an APC group (n=10) and a control group with normal saline (n=10). Injections of these solutions into rats were performed 30 minutes before the planned-I/R injury. Cardiac performance after the procedure was evaluated by echocardiography or indices with Langendorff apparatus. Coronary flow (CF) was measured in the global I/R injury model. Western blotting was performed to detect the change of AKT1 signal in myocardium after global I/R injury. RESULTS: LV FUNCTION IMPROVED SIGNIFICANTLY IN THE APC GROUP: %EF at 2 weeks after procedure, 70.8%± 4.5% vs. 56.5%± 0.7%; APC vs. control; p<0.01. Percent LV development pressure (LVDP) also improved in the APC group significantly, 88.8%± 45.3% vs. 28.1%± 15.4%; APC vs. control; p<0.01. In APC group, %CF improved significantly, 88.5%± 15.8% vs. 65.0%± 13.4%; APC vs. control; p<0.01. It was enhanced significantly when acetylcholine was administered; % CF: 103.5%± 9.9% vs. 87.0%± 12.1%; APC vs. control; p<0.05. Western blotting revealed that APC significantly induced activation of phosphorylated AKT1 in myocardium (p<0.05). CONCLUSIONS: APC has a novel effect to protect myocardium and cardiac performance against I/R injury through improvement of endothelial function and activation of AKT1.

Efficacy of Damus-Kaye-Stansel procedure in patients with univentricular heart associated with ventriculo-arterial discordance and excessive pulmonary blood flow.

Pulmonary artery banding (PAB) and ventriculo-arterial discordance (VAD) were reported to be risk factors of subaortic stenosis in univentricular heart. The aim of this study was to evaluate efficacy of Damus-Kaye-Stansel (DKS) anastomosis. Of all 89 patients undergoing total cavo-pulmonary connection (TCPC) in our center since April 1996, 38 had VAD with high pulmonary blood flow, and had received PAB. Twenty-one of 38 had undergone DKS anastomosis due to subaortic stenosis or due to morphological hypertrophy of the outlet septum (DKS group); the other 17 had not yet (no-DKS group). Percentage end-systolic volume of the systemic ventricle and percentage subaortic lesion in both groups significantly decreased after TCPC (P<0.01). Pressure gradient across systemic outflow tract after TCPC was low in both groups at rest. The gradient in DKS group did not differ from those in control group with ventriculo-arterial concordance (VAC) (P>0.1). Ventricular outflow tract after DKS anastomosis might behave like that of VAC even when dobutamine is loaded, suggesting that the anastomosis should be carried out in many patients with this entity even if stenosis across systemic ventricular outflow is not significant, considering possible stenosis in the future.

Granulocyte colony-stimulating factor prevents reperfusion injury after heart preservation.

BACKGROUND: Heart transplantation is an accepted method of treatment for selected patients with end-stage heart disease. Making prolonged heart preservation safer will benefit patients awaiting heart transplantation. Granulocyte colony-stimulating factor (G-CSF) exhibited protective effects against myocardial ischemia-reperfusion injury mediated through the Janus kinase (Jak)/(signal transducer and activator of transcription (Stat) pathway. We examined whether pharmacologic preconditioning with G-CSF improves cardiac function after heart preservation. METHODS: Male rats were divided into four groups: group A, saline injection; group B, G-CSF, 10 microg/kg; group C, G-CSF, 100 microg/kg; and group D, G-CSF, 100 microg/kg plus AG490 (a selective Jak2 inhibitor), 1 mg/kg. The G-CSF and AG490 were given intravenously for 3 consecutive days. Four hours after the final treatment, isolated rat hearts underwent 12 hours of hypothermic (4 degrees C) preservation, followed by 60 minutes of normothermic reperfusion. RESULTS: Stat3 phosphorylation was observed in the heart at 15 minutes after G-CSF treatment in group C, but this was attenuated by additional treatment with AG 490 in group D. Compared with group A, group C exhibited significant recovery of left ventricular pressure, maximum positive rate of left ventricular developed pressure (Max dP/dt), and coronary flow (p < 0.05, respectively), as well as lower creatine phosphokinase leakage during reperfusion (p < 0.05). Group B and group D did not show significant hemodynamic recovery during reperfusion. In group C, increased Bcl-xL and decreased Bax expressions as well as decreased terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling (TUNEL)-positive cardiomyocytes were observed after reperfusion. Immunohistochemical examination showed significantly increased capillary density before hypothermic preservation in group C, but not in other groups. CONCLUSIONS: Pharmacologic preconditioning with G-CSF protected hearts from prolonged hypothermic ischemia-reperfusion injury.