Prostaglandin E1 induces vascular endothelial growth factor-1 in human adult cardiac myocytes but not in human adult cardiac fibroblasts via a cAMP-dependent mechanism

Prostaglandin E(1) (PGE(1)) has been used to treat pulmonary hypertension and peripheral artery occlusive disease and has been successfully employed for pharmacological bridging to transplantation in patients with chronic end-stage heart failure. In addition to its vasoactive effects PGE(1) was shown to stimulate angiogenesis in animal models. Recently we showed that PGE(1)-induced angiogenesis in hearts of patients with ischemic heart disease. We proposed that the angiogenic action of PGE(1) is mediated by vascular endothelial growth factor (VEGF). In the present paper we studied a possible effect of PGE(1) on the expression of VEGF-1 in cultured human adult cardiac myocytes (HACM) and cultured human adult cardiac fibroblasts (HACFB), respectively, to identify a cellular source of VEGF-1 in patients treated with PGE(1). We also aimed to delineate mechanisms involved in a possible regulation of VEGF-1 by PGE(1) in these cells. When HACM, isolated from human myocardial tissue, were treated with PGE(1), a significant up to 3-fold increase in VEGF-1 production could be observed. These results could be confirmed on the level of specific mRNA expression as determined by real-time polymerase chain reaction. The effect of PGE(1) on VEGF-1 expression could be blocked by H089, an inhibitor of cAMP-dependent protein kinase A. In HACFB, also isolated from human myocardial tissue, no effect of PGE(1) on VEGF-1 production was seen. If this effect of PGE(1) is also operative in the in vivo situation, one could speculate that cardiac myocytes could be a cellular source of PGE(1)-induced VEGF-1 expression in patients treated with this drug.     

Drug-eluting stent fracture occurred within 2 days after stent implantation

We report our experience with 256-slice cone-beam computed tomography following selective coronary arterial bolus injection in pigs, which distinguished the segmented left ventricular (LV) myocardium supplied by each coronary artery into three parts more clearly than with other modalities. Two pigs were anesthetized and catheters positioned in the left anterior descending branch (LAD) of the coronary artery in pig 1 and the left circumflex branch (LCx) in pig 2. 10 ml of iodinated contrast material diluted with 40 ml of saline was injected at a rate of 3 ml/s. Entire heart scanning was started simultaneously and continued for 25 s. We selected the most static images of the LV at around 5 s after contrast injection. Axial source and multiplanar reconstruction images from the right anterior oblique projection clearly revealed tricolored, segmented LV myocardial enhancement of the anterior and apical walls and inter-ventricular septum in pig 1, and the lateral and posterior walls in pig 2. We were able to identify the borders between the LV myocardium supplied by the LAD, the LCx and the right coronary artery, respectively, and this technique may facilitate new cardiovascular diagnoses.     

Induction of myocardial biglycan in heart failure in rats--an extracellular matrix component targeted by AT(1) receptor antagonism

OBJECTIVE: Cardiac remodelling associated with congestive heart failure typically involves dilatation of the ventricular cavities, cardiomyocyte hypertrophy and alterations of extracellular matrix. Biglycan is an extracellular proteoglycan with several recently appreciated functions including cell adhesion, collagen fibril assembly, and growth factor interactions. The aims of this study were to investigate the regulation of biglycan expression and to elucidate the site(s) of synthesis of biglycan in myocardial tissue in an experimental model of heart failure (HF). METHODS: Myocardial tissue samples were obtained from rats with myocardial infarction (MI) subsequent to ligation of the left coronary artery. Northern blot analysis and real-time quantitative RT-PCR were employed to investigate mRNA levels. The cellular distribution of biglycan was analysed by in situ hybridisation and immunohistochemistry. RESULTS: Myocardial biglycan mRNA levels in non-ischemic tissue of both left and right ventricles of heart failure rats were substantially elevated as compared to sham-operated rats. Although expression levels peaked 7 days after MI (13-fold increase compared to the sham group, P<0.05), substantial elevations of biglycan mRNA were observed throughout the study period. Analysis of cellular distribution revealed that biglycan expression was confined to myocardial fibroblasts and vascular endothelial cells. In cardiac fibroblasts isolated from failing hearts, biglycan mRNA levels were markedly elevated compared with fibroblasts from sham-operated rats. In addition, in rats with ischemic heart failure treatment with the AT(1) receptor antagonist losartan (12.5 mg.kg(-1) b.i.d. per os, for 25 days) prevented the increase of myocardial biglycan as well as TGF-beta(1) mRNA. CONCLUSION: This report demonstrates global induction of myocardial biglycan mRNA in heart failure. Myocardial biglycan expression could be targeted by AT(1) receptor antagonism, an intervention well documented to halt cardiac remodelling in heart failure. Furthermore, the study provides evidence that angiotensin II is a regulator of biglycan expression in cardiac fibroblasts.     

Collateral vessel development after right ventricular infarction in the pig

Although the right coronary artery supplies both ventricles in the pig, a gradual proximal right coronary occlusion produces infarction in the left ventricle, whereas the right ventricle is usually spared. This study evaluates the influence of right ventricular hypertension and hypertrophy (RVHH) on the occurrence of right ventricular infarction and the difference in the rate and extent of collateral vessel development after gradual right coronary occlusion in pigs with (RVHH group) and without (control group) increased right ventricular pressure and mass. Right ventricular hypertension and hypertrophy were induced by pulmonary arterial banding which raised right ventricular systolic pressure from 24 to 74 mm Hg and doubled right ventricular mass in 4 weeks. Right coronary occlusion was produced with an ameroid constrictor in 24 control group pigs and 15 RVHH pigs. Serial selective coronary cineangiograms on days 4, 8, 14, 21 and 28 after ameroid constrictor placement showed no difference in first appearance of collateralization to the occluded right coronary artery. Total collateralization, which was present in all pigs studied in the control group by days 21 and 28, was present in only 57 percent of the RVHH group at the same time. Although left ventricular infarction occurred in all animals in both groups, right ventricular infarction was not found in the control group but was seen in 80 percent of the RVHH group. There was no correlation between the degree of collateralization seen and the size of the right ventricular infarction found. Experimentally induced right ventricular hypertrophy and hypertension make the right ventricle susceptible to infarction and impeded total collateral filling of the occluded right coronary artery in some of the animals studied.     

Dietary fish oil reduces the occurrence of early afterdepolarizations in pig ventricular myocytes

Fish oil reduces sudden cardiac death in post myocardial infarction patients. Life-threatening arrhythmias in heart failure are associated with repolarization abnormalities leading to EAD(1) formation. We examined the effects of incorporated fish oil omega3-PUFAs(2) on EAD formation in pig myocytes. Pigs were fed a diet rich in fish oil or sunflower oil (control) for 8 weeks. Myocytes were isolated by enzymatic dissociation and patch-clamped. Susceptibility to EAD formation was tested using E4031 (5 microM), a blocker of I(Kr). The fish oil diet in pigs resulted in increased incorporation of omega3-PUFAs in the sarcolemma of the myocytes compared to the control diet and caused a reduced occurrence of E4031-induced EADs in pig myocytes. A shorter action potential, a reduced action potential prolongation in response to E-4031 and a reduced reactivation of I(Ca,L) by omega3-PUFAs may explain the observed reduction in EADs. A diet rich in fish oil protects against EAD formation.     

Expression and distribution of atrial natriuretic polypeptide in the ventricles of children with myocarditis and/or myocardial infarction secondary to Kawasaki disease: immunohistochemical study

We studied the expression and distribution of atrial natriuretic polypeptide in the ventricles of 27 autopsied children with Kawasaki disease. Fourteen of the children had died in the acute stage of the disease. Three without any coronary artery aneurysms died due to myocarditis, while 11 with coronary artery aneurysms also had myocarditis but died of coronary heart disease. Histologic evidence of acute myocardial infarction was noted in three children who died of coronary heart disease. In the 14 children with acute-stage deaths, no abnormal expression of atrial natriuretic polypeptide was noted in the ventricles, despite the presence of heart failure in seven of them for 2 to 22 days before death. The other 13 patients had coronary artery aneurysms and died in the healed stage. In three patients with granulation tissue and congestive heart failure, myocytes in foci around the granulations were moderate to markedly positive for atrial natriuretic polypeptide. These three patients died over 8 days after the onset of their first myocardial infarct. Of 10 patients with old myocardial infarction, four had a history of congestive heart failure. They demonstrated moderate or marked atrial natriuretic polypeptide expression in extensive regions around sites of massive fibrosis, and foci of slight expression in the inner third of the noninfarcted region of the ventricle. In the other six patients without congestive heart failure, there was slight or moderate expression in foci around sites of massive fibrosis. We concluded that the expression of atrial natriuretic polypeptide appeared more than 1 week after the onset of acute myocardial infarction in the ventricles of children with Kawasaki disease who died in the healed stage.(ABSTRACT TRUNCATED AT 250 WORDS)     

不同剂量卡维地洛干预对心肌梗死后心力衰竭大鼠心肌细胞凋亡和凋亡相关基因表达的影响

目的 :探讨不同剂量卡维地洛 (CAR)对心肌梗死 (MI)后大鼠心肌细胞凋亡的影响及CAR治疗充血性心力衰竭 (CHF)的作用机制。方法 :将雄性Waistar大鼠前降支结扎 ,于术后 1周开始分别予大剂量CAR[HCAR组 ,6 0mg/ (kg·d) ]和小剂量CAR[LCAR组 ,6mg/ (kg·d) ]干预 7周 ,观察不同剂量CAR对大鼠血流动力学参数、心肌细胞凋亡、Fas、Fas配体 (FasL)和Bcl 2mRNA表达的影响。结果 :CAR可改善心功能指标 ,降低心肌细胞凋亡指数、Fas及FasL的mRNA水平 ,上调Bcl 2表达 ,其中对心肌细胞凋亡指数、Fas及Bcl 2mRNA表达的影响以HCAR组明显。结论 :CAR可有效地减少MI后心肌细胞凋亡 ,防治CHF ,效果以大剂量明显 ,这可能与其对凋亡相关基因表达影响的差异有关     

扶正化瘀胶囊对心肌梗死大鼠心肌缝隙连接蛋白43表达的影响

目的研究扶正化瘀胶囊对心肌梗死大鼠心肌缝隙连接蛋白43(connexin43,CX43)表达的影响。方法SD雄性大鼠随机分为假手术组、模型组以及扶正化瘀胶囊组和卡托普利组,每组各6只,采用结扎左冠状动脉前降支造成心肌梗死。术后10d开始灌胃给药,持续8周。用免疫组织化学方法观察心肌CX43表达的变化。结果在心肌梗死区域内,模型组与假手术组比较,CX43排列紊乱,阳性表达面积、平均光密度值和积分光密度均显著低于假手术组(P<0.01)。在梗死边缘区,扶正化瘀胶囊组CX43平均光密度值高于模型组(P<0.01),积分光密度高于模型组(P<0.05),CX43排列紊乱有所减轻,阳性表达面积与模型组无统计学意义。卡托普利组CX43平均光密度值高于模型组(P<0.01),积分光密度和阳性表达面积均高于模型组(P<0.05),CX43排列紊乱也有减轻。结论扶正化瘀胶囊能够部分改善心肌梗死大鼠心肌的CX43重构。     

Induction of myocardial neoangiogenesis by human growth factors. A new therapeutic approach in coronary heart disease

Currently available approaches for treating human coronary heart disease aim to relieve symptoms and the risk of myocardial infarction either by reducing myocardial oxygen demand, preventing further disease progression, restoring coronary blood flow pharmacologically or mechanically, or bypassing the stenotic lesions and obstructed coronary artery segments. Gene therapy, especially using angiogenic growth factors, has emerged recently as a potential new treatment for cardiovascular disease. Following extensive experimental research on angiogenic growth factors, the first clinical studies on patients with coronary heart disease and peripheral vascular lesions have been performed. The polypeptides fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) appear to be particularly effective in initiating neovascularization (neoangiogenesis) in hypoxic or ischemic tissues. The first clinical study on patients with coronary heart disease treated by local intramyocardial injection of FGF-1 showed a 3-fold increase of capillary density mediated by the growth factor. Also, angiogenic growth factor injection intramyocardially as sole therapy for end-stage coronary disease showed an improvement of myocardial perfusion in the target areas as well as a reduction of symptoms and an increase in working capacity. Angiogenic therapy of the human myocardium introduces a new modality of treatment for coronary heart disease in terms of regulation of blood vessel growth. Beyond drug therapy, angioplasty and bypass surgery, this new approach may evolve into a fourth principle of treatment of atherosclerotic cardiovascular disease.     

实验性急性心肌梗死中Bax和Bcl-2基因对心肌细胞凋亡的调控

目的 探讨急性心肌梗死（AMI）中Bax和Bcl-2基因对心肌细胞凋亡的调控作用。方法 新西兰兔48只，随机分为不结扎冠状动脉的正常对照组及结扎冠脉后1h，2h,3h,4h,6h,8h,12h共7组。TUNEL法检测梗死区心肌细胞凋亡，免疫组化法检测Bax和Bcl-2蛋白在心肌细胞中的表达水平。结果 急性心肌梗死心肌细胞凋亡数在冠脉结扎后1h开始增多，4h达高峰，以后逐渐下降，12h己降至正常。有Bax蛋白表达的阳性心肌细胞数与心肌细胞的凋亡数呈正相关，有Bcl-2蛋白表达的阳性心肌细胞数与心肌细胞的凋亡数呈负相关。结论 AMI免梗死区心肌细胞存在明显的凋亡现象，且受Bax蛋白上调、Bcl-2蛋白质下调，两作用相反，共同调节有着心肌细胞的凋亡。     

Transforming growth factor beta inhibition increases mortality and left ventricular dilatation after myocardial infarction

BACKGROUND: Transforming growth factor (TGF)-beta is a locally generated cytokine involved in healing processes and tissue fibrosis, all relevant for cardiac remodeling and the development of heart failure after myocardial infarction (MI). However, data regarding the function of TGF-beta after ischemic injury are inconclusive. METHODS AND RESULTS: We tested the effect of TGF-beta inhibition by application of a blocking antibody in mice with MI. Starting 1 week before or 5 days after coronary artery ligation mice were treated with intraperitoneal injections of an anti-TGF-beta (5 mg/kg bodyweight 1D11, Genzyme) or control antibody. Mortality over 8 weeks was significantly higher in the groups treated with the anti-TGF-beta antibody. Both, pre or post MI treatments were associated with increased left ventricular dilatation after MI as determined by serial echocardiography. In anti-TGF-beta treated mice collagen production decreased and matrix-metalloproteinase expression increased. However, the expression of TGF pro-inflammatory cytokine TNF-alpha was not altered by the treatment. Anti-TGF-beta treatment before or after coronary artery ligation increases mortality and worsens left ventricular remodeling in mice with non-reperfused MI. The detrimental effects of TGF-beta inhibition may be mediated by alterations in extracellular matrix remodeling.     

Glycoprotein 130 ligand oncostatin-M induces expression of vascular endothelial growth factor in human adult cardiac myocytes

OBJECTIVE: In murine and rat cardiac myocytes the gp130 system transduces survival as well as hypertrophic signals and via induction of the expression of the potent angiogenic factor VEGF in these cells also indirectly contributes to cardiac repair processes through the development of new blood vessels. There are, however, species differences in receptor specificity and receptor crossreactivity in the gp130-gp130 ligand system. We asked whether gp130 signaling is also involved in the regulation of VEGF in human cardiac myocytes and if so which gp130 ligands are critical for such an effect. METHODS: Human adult cardiac myocytes (HACMs) were isolated from myocardial tissue and characterised by positive staining for myocardial actin, troponin-I and cardiotin. HACMs were treated with the gp130 ligands CT-1, IL-6, LIF or OSM and VEGF-1 was determined by a specific ELISA in the conditioned media of these cells. RT-PCR and Western blot analysis was used in order to detect gp130, IL-6-receptor, LIF-receptor or OSM-receptor specific protein and mRNA in human adult cardiac myocytes and for detection of VEGF-1 specific mRNA in cardiac myocytes after incubation with OSM. Pieces of myocardial tissue were incubated ex vivo in the presence and absence of OSM and VEGF was determined in supernatants of these cultures and immunohistochemistry was performed on the tissue using specific antibodies for VEGF-1. Immunohistochemistry was also employed to detect VEGF in sections from a healthy human heart and in a heart from a patient suffering from acute myocarditis. RESULTS: OSM, but not CT-1, IL-6 or LIF increased VEGF-1 production in human adult cardiac myocytes dose-dependently derived from five different donors. This selective stimulation of VEGF by gp130 ligands was also reflected by a specific receptor expression on these cells. We detected high levels of mRNA for gp130 and the OSM receptor in freshly isolated human cardiac myocytes but only low amounts of mRNA for the IL-6 receptor whereas mRNA for the LIF receptor was hardly detectable by RT-PCR. OSM receptor and IL-6 receptor were also detectable by Western blotting whereas LIF receptor was only present as a faint band. OSM also increased the expression of VEGF-1 mRNA in cardiac myocytes. When pieces of human myocardial tissue were incubated with the gp130 ligands in an ex vivo model only OSM resulted in an increase in VEGF-1 in the supernatants of these cultures. Furthermore, VEGF increased in tissue samples treated with OSM in cardiac myocytes as evidenced by immunohistochemistry. In addition, we found increased VEGF-1 expression in myocardial tissue from a patient suffering from acute myocarditis. CONCLUSION: The gp130-gp130 ligand system is also involved in VEGF regulation in human cardiac myocytes and OSM is the gp130 ligand responsible for this effect in the human system whereas LIF and CT-1 which had been shown to regulate VEGF expression in mouse and rat cardiac myocytes had no effect. Thus we have added OSM, which is produced by activated T lymphocytes and monocytes, to the list of regulatory molecules of VEGF production in the human heart. Our results lend further support to the notion that besides hypoxia, inflammation via induction of VEGF through autocrine or paracrine pathways plays a key role in (re)vascularisation of the myocardium.     

Decreased expression of Na+/H+ exchanger isoform 1 (NHE1) in non-infarcted myocardium after acute myocardial infarction

Although cardiac NHE1 is activated during myocardial ischemia and reperfusion injury, little is known about changes in expression in non-infarcted myocardium after acute myocardial infarction (AMI). The purpose of this study was to examine left ventricular function and region dependent NHE1 expression after myocardial infarction. Therefore, we produced two AMI models in rats, a small infarction model which was continuously ligated at the branches of the left coronary artery, and an extensive infarction model continuously ligated at the root of the artery. We examined NHE1 mRNA expression using RNase protection assay and protein levels using Western blot analysis in non-infarcted myocardium during the 24 hour period after AMI. The level of NHE1 mRNA and protein expression in the whole heart including the infarcted myocardium did not change after a small infarction. On the other hand, in the case of an extensive infarction, the levels of NHE1 mRNA and protein expression decreased significantly by 21.5% (P<0.05) and by 22.0% (P<0.05), respectively, in non-infarcted myocardium. Left ventricular systolic pressure (LVSP) decreased significantly by 13% and 38% with the branch and root ligation, respectively. However, left ventricular end-diastolic pressure (LVEDP) only increased with the root ligation. These results indicate that NHE1 expression decreased in response to extensive myocardial infarction only in non-infarcted myocardium. The present study may be important in furthering the understanding of NHE1 in myocardial infarction and suggests that decreased expression of NHE1 in non-infarcted myocardium may decrease the extent of cardiac cell injury.     

Fractalkine upregulates intercellular adhesion molecule-1 in endothelial cells through CX3CR1 and the Jak Stat5 pathway

Fractalkine (FKN) is a membrane-bound chemokine that can be released by proteolysis to produce soluble FKN (s-FKN). FKN and its receptor, CX3CR1, are believed to be important factors in atherosclerosis and may play a role in acute inflammatory responses. Although FKN is expressed on endothelial cells (ECs), CX3CR1 is reported to reside mainly on certain leukocyte populations. RT-PCR and Western blotting demonstrated that both human coronary artery and umbilical vein ECs expressed CX3CR1 mRNA and protein. Confocal microscopy showed that CX3CR1 was located at the cell membrane and to a lesser extent in the cytoplasm. Following exposure of both types of ECs to hypoxia and reoxygenation, FKN expression increased rapidly and s-FKN was shed into the culture medium. The addition of s-FKN protein to cultured ECs resulted in a dose-dependent increase in intercellular adhesion molecule (ICAM)-1 mRNA. Perfusion of mouse hearts with s-FKN protein increased expression of ICAM-1 protein in vascular endothelium. Transfection of ECs with CX3CR1-interfering RNA to knockdown the receptor resulted in decreased ICAM-1 expression after s-FKN stimulation. In addition, when ECs were stimulated with s-FKN, greater adhesion of human neutrophils to the ECs was observed. This increase was ICAM-1 dependent and was blocked by CX3CR1 knockdown. Following exposure to s-FKN, ECs exhibited increased phosphorylation of Jak2 and Stat5 and the ICAM-1 expression induced by s-FKN was blocked by silencing of Stat5 with small interfering RNA. Vascular ECs express both FKN and its receptor CX3CR1. s-FKN is shed from ECs following hypoxia/reoxygenation and acts through CX3CR1 on ECs to increase ICAM-1 expression and promote neutrophil adhesion through activation of the Jak-Stat5 pathway.     

A strategy of retrograde injection of bone marrow mononuclear cells into the myocardium for the treatment of ischemic heart disease

OBJECTIVE: Bone marrow cells implantation (BMI) has been reported to efficiently improve ischemic heart disease. However, BMI strategies are generally invasive. To establish a BMI strategy for ischemic heart disease, we performed implantation of autologous cryopreserved mononuclear cells (MNCs) from bone marrow (BM) retrogradely into the myocardium via the coronary vein in pigs with acute myocardial infarction (AMI) and old myocardial infarction (OMI). METHODS: BM cells were harvested from the pigs' fumurs. MNCs were collected by centrifugation and were cryopreserved. Anterior myocardial infarction was induced by occlusion of the midportion of the left anterior descending coronary artery without surgical intervention. Frozen BM cells were quickly thawed and injected retrogradely via the coronary vein into the myocardium through a single balloon infusion catheter 6 h and 2 weeks after the induction of infarction. Four weeks after implantation, coronary arteriograms were obtained, cardiac function was analyzed with the use of a conductance catheter, and histopathologic analysis was performed with a confocal laser microscope. Plasma levels of natriuretic peptides and angiogenic growth factors were measured after BMI. RESULTS: Flow cytometric analysis revealed that 90% of cryopreserved BM cells were viable in vitro. Labeled BM cells were entirely distributed around in the infarcted area of maycardium in pigs. BMI increased collateral neovascuralization in infarcted hearts. BMI significantly improved cardiac function in AMI with BMI and OMI with BMI groups. BMI also increased the formation of microcapillary arteries in infarcted hearts. Levels of natriuretic peptides were significantly decreased, and levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2) were significantly increased after BMI. Confocal laser microscopy revealed the presence of proliferative and activated myocardial cells in infarcted hearts after BMI. CONCLUSION: The retrograde infusion of cryopreserved BM cells into myocardium efficiently induced angiogenesis and improved cardiac function in pigs with AMI or OMI. These results suggest that the present strategy of BMI will be safe and feasible as an angiogenic cell therapy for ischemic heart disease.     

Myocardial surface PO2--an indicator of myocardial tissue oxygenation?

The validity of myocardial surface tissue PO2 (PtO2) as a reliable indicator of transmural myocardial tissue oxygenation was studied in six anaesthetised, open chest pigs. Epicardial surface PtO2 was correlated with other variables of myocardial tissue oxygenation such as regional blood flow, coronary venous PO2, O2 saturation, PCO2 and regional myocardial lactate extraction. The study design was based on an experimental model in which the effects of a pacing induced tachycardia on tissue oxygenation of ischaemic and normally supplied myocardium were measured. Two platinum multiwire surface electrodes were placed on the epicardium, on the areas supplied by the left anterior descending coronary artery (LAD) and the left circumflex coronary artery (CX). The LAD was constricted to reduce mean surface PtO2 in the LAD area to about 50% of its baseline value. This did not affect surface PtO2 in the CX area. The reduction of surface PtO2 in the LAD area was associated with decreases in coronary venous PO2 and O2 saturation and with increases in coronary venous lactate and PCO2. Subendocardial regional blood flow and the subendocardial to subepicardial flow ratio were significantly lower than in the CX area. Increasing the heart rate by pacing (+45 beats.min-1) led to an increased degree of ischaemia as shown by fall in surface PtO2 in the LAD area to values around zero kPa, by marked increase in coronary venous lactate and PCO2, by reduction in total (-10%) and subendocardial (-40%) LAD flow and by deterioration of the subendocardial to subepicardial flow ratio. The increased degree of ischaemia was not accompanied by an increase in O2 extraction. The marked decrease in surface PtO2 occurred in spite of a slight increase in the subepicardial regional blood flow (+10%); thus the increase in O2 delivery was not sufficient to meet the increase in O2 demand. Total flow was increased by 27% in the CX area without changes in the subendocardial to subepicardial flow ratio and in the surface PtO2 values. When pacing was stopped, surface values of PtO2 in the LAD area returned to prepacing values, as did lactate extraction and coronary venous PCO2. Clear and close relationships with surface PtO2 were found for regional lactate extraction, coronary venous PCO2 and the normalised subendocardial RBF. Poor or no correlations were found for the normalised subepicardial regional blood flow, the coronary venous O2 saturation and the absolute values of subendocardial and subepicardial regional blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)     

Eplerenone suppresses neointimal formation after coronary stent implantation in swine

BACKGROUND: Enhanced extracellular matrix accumulation rather than cell proliferation contributes to later stages of in-stent restenosis. Aldosterone itself has been shown to increase cardiovascular fibrosis, therefore, we studied the suppressive effects of eplerenone, a new aldosterone receptor antagonist, on neointimal hyperplasia after coronary stent implantation in swine. METHODS: Palmatz-Shatz stents were implanted in the left anterior descending artery of 36 pigs. One hundred milligrams of Eplerenone was orally administered from 1 week before, to 4 weeks after stent implantation in Group E (n=18), and vehicle was given to Group C (n=18). Pigs were sacrificed 1 or 4 weeks after stent implantation. The number of infiltrating macrophages was calculated at 1 week. Morphometrical analysis was performed to measure the area of each layer, and %area of fibrosis and mRNA for collagen I, III and TGF-beta was analyzed by RT-PCR at 4 weeks. RESULTS: The number of infiltrating macrophages was less in Group E than in Group C (p<0.01). The overall size of coronary arteries at 4 weeks was similar in both groups. However, the luminal area was larger in Group E than in Group C (p<0.05), and the intimal area was smaller in Group E than in Group C (p<0.05). The %area of fibrosis was significantly less in Group E than in Group C at 4 weeks (p<0.01). In Group E, the expression of mRNA for collagen I, III and TGF-beta was significantly reduced. CONCLUSION: Orally administered eplerenone attenuated collagen accumulation within the neointima, thereby inhibiting neointimal hyperplasia after stent implantation.     

置入铜丝缠绕型支架制作猪急性心肌梗死模型

目的探讨在猪冠状动脉内置入铜丝缠绕型支架制作急性心肌梗死模型的可行性,建立一种新的急性心肌梗死模型方法。方法16头中国实验用小型猪经股动脉穿刺,在前降支置入自制的铜丝缠绕型支架。1周内观察心肌肌钙蛋白I、心电图、心脏超声和冠状动脉造影。然后处死取出心脏,取目标冠状动脉和心肌,做病理学检查。结果16头小型猪均发生了心肌梗死。梗死发生后死亡2头,其中1头在术后8 h猝死,1头在术后1周冠状动脉造影复查时死于麻醉中;其余14头均存活在1周以上,完成复查,总的成功率为87.5%。结论该模型制作具有操作简单、创伤小、成本低、死亡率低、成功率高等诸多优点,可作为较好的实验研究动物模型。