[Evaluation of early results of re-coronary artery bypass grafting].

Redo surgery is more difficult than primary operation. From January 2002 to December 2008, 19 patients underwent re-coronary artery bypass grafting (re-CABG) [6.4 percent of the total CABG] : CABG (16) and CABG + combined procedure (3). Approach of redo operation consists of, median re-sternotomy (5), left posterolatelal thoracotomy (4), via diaphragm (6) and left anterior small thoracotomy (LAST) [1]. In a redo operation, we consider different approaches from the primary operation to avoid injury during dissection of adhesive tissue. Particularly in simple CABG, 11 of the 16 patients (68.8%) were operated on adopting a different approach from the primary operation. The femoral artery and vein were exposed before median re-sternotomy. There was no serious adverse event nor operative death, and all grafts were well patent. Redo CABG can be performed with a low risk.

[Off-pump coronary artery bypass via left thoracotomy in patient with infective pancreatic fistula after surgery for bile duct carcinoma; report of a case].

A 62-year-old man with infective pancreatic fistula after surgery for bile duct carcinoma underwent off-pump coronary artery bypass (OPCAB) through left thoracotomy to avoid the use of cardiopulmonary bypass and the postoperative mediastinitis, since this patient has infective pancreatic fistula close to the xiphoid process. The coronary arterial revascularizations were performed: left internal thoracic artery to left anterior descending branch and saphenous vein graft to descending thoracic aorta. The aortic mechanical anastomosis device, aortic connector, was utilized the proximal anastomosis of saphenous vein graft so as to avoid aortic clamp, while the distal anastomoses were completed with stabilizer and apical retraction device. Postoperative angiogram showed both grafts were patent. No signs of infection or recurrence of malignant neoplasm was observed. OPCAB via left thoracotomy is one of useful options for patients in whom median sternotomy is not suitable approach for myocardial revascularizations.

[Aortic root replacement with free-style stentless valve for aorto-left and right ventricular communication due to infective endocarditis; report of a case].

Aortic root abscess remains a major determinant of both early and late results of surgical treatment of endocarditis. This complication rarely progresses to intracardiac shunt followed by cardiac failure. We report a surgical case of a 40-year-old man, who had been diagnosed as prosthetic valve endocarditis with aortic root abscess ruptured into left and right ventricle creating aorto-left and right ventricular communication. Because of complete debridment of infective and/or dead tissue, aortic root replacement was required. We used free-style stentless valve, xenograft, since homograft was not available at the time of operation. We believe that this prosthesis has easier handling and is more resistant to infection, therefore, it might be an option for infective endocarditis with aortic root abscess.

Isolation technique for stroke prevention in patients with a mobile atheroma.

Mobile atheroma in the proximal aorta is a risk factor for brain complication after cardiovascular operation. We report a new technique of replacing the ascending and transverse aorta by establishing selective hypothermic antegrade cerebral perfusion. After cooling, cerebral vessels are clamped and systemic perfusion is started. This technique was applied in 5 patients. All patients woke up normally and recovered without neurologic complication.

Thymic carcinoma with tumor thrombus into the superior vena cava.

Tumor thrombus into the vena cava have been reported in cases with renal cell carcinoma, thyroid tumor and in those with thymoma. These tumors are frequently invasive and continuous from the main tumor that shows direct vessel wall invasion. Here, we report a case of thymic carcinoma with superior vena cava syndrome, which was caused by a tumor thrombus in the superior vena cava without vessel wall invasion. The main mediastinal tumor did not show innominate vein invasion, and the superior vena cava syndrome was a result of separate tumor thrombus that was free of vessel wall invasion. The tumor thrombus could be removed through a simple venotomy. To prevent stenosis in the superior vena cava and the left innominate vein, we used a pericardial patch to close the venotomy site.

Combination of a brief irrigation with tissue factor pathway inhibitor (TFPI) and adenovirus-mediated local TFPI gene transfer additively reduces neointima formation in balloon-injured rabbit carotid arteries.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a physiological antagonist of TF. We tested whether a brief irrigation with TFPI protein (rTFPI) or TFPI gene transfer into injured arteries would suppress TF activity and reduce fibroproliferative changes and investigated whether a combination of these methods would show an additive effect. METHODS AND RESULTS: We prepared adenoviruses expressing either TFPI (AdTFPI) or bacterial ss-galactosidase (AdLacZ). Rabbit carotid arteries were balloon-injured and either infected with AdTFPI (or AdLacZ) or irrigated briefly with rTFPI (or saline). After injury, TF activity in arteries increased and was sustained; however, it was suppressed during the initial 24 hours by rTFPI irrigation (but not by gene transfer) and for a substantial period of time by TFPI gene transfer (but not by rTFPI irrigation). Four weeks later, the ratio of the intimal to medial areas was 34.3+/-8.7% (mean+/-SD, n=14) in saline-treated arteries and 33.3+/-4.2% in AdLacZ-infected arteries (P:=NS versus saline). However, it was reduced to 25.5+/-8.5% in rTFPI-irrigated arteries (P:<0.01 versus saline) and to 20.7+/-5.3% in AdTFPI-infected arteries (P:<0.01 versus AdLacZ). With a combination of irrigation and gene transfer, the ratio was further reduced to 12.6+/-4.7% (P:<0.01 versus rTFPI, P:<0.05 versus AdTFPI). Systemic coagulation status was not affected in these animals. CONCLUSIONS: A combination of rTFPI irrigation and TFPI gene transfer overcomes the shortcomings shown by each method when used alone and achieves a full coverage of TF activity suppression, thereby enhancing their therapeutic effects without systemic side effects. This combination may be an effective strategy for the prevention of thrombosis and proliferative changes after angioplasty in humans.

Concomitant abdominal aortic aneurysm repair and cholecystectomy. Combination of retroperitoneal aortic reconstruction and gassless laparoscopic cholecystectomy.

The coexistence of cholelithiasis and abdominal aortic aneurysm is not uncommon. However, cholecystectomy at the time of abdominal aortic reconstruction has generally been delayed because of the potential contamination of the graft. The case described here had concomitant cholelithiasis and abdominal aortic aneurysm, both of which were required to be treated, and was successfully treated with a combination of retroperitoneal abdominal aortic reconstruction and gasless laparoscopic cholecystectomy.

Mitral valve replacement and subsequent composite graft replacement of the aortic root for infantile Marfan syndrome.

The cardiovascular lesions commonly seen in Marfan syndrome can frequently be the primary cause of premature death. Cardiac lesions involving both the mitral valve and the aortic root are commonly observed among patients diagnosed during early infancy, as so-called infantile Marfan syndrome. Since the lesions tend to progress rapidly with the end results of high morbidity and mortality, the majority of patients require surgical intervention at a young age. However, patients who undergo surgical intervention for both lesions during the first decade of life have been rarely reported in literature. In this report, we present a case of a 9-year-old boy who underwent aortic root replacement with a composite graft at 3.5 years after a prior prosthetic valve replacement of the mitral valve. Although the immediate result was satisfactory, the long-term result remains to be seen.

Suppression of the tissue factor-dependent coagulation cascade: a contributing factor for the development of intratumoral hemorrhage in glioblastoma.

To clarify factors that may contribute to the development of intratumoral hemorrhage, we analyzed the expression of tissue factor (TF), an initiator of the extrinsic coagulation pathway, and of tissue factor pathway inhibitor (TFPI) in glioblastomas with or without massive intratumoral hematoma. Among 196 glioma cases reviewed, there were 13 with macroscopic intratumoral hemorrhage. We focused on the glioblastomas and used immunoblot- and immunohistochemical methods to compare the expression of TF and TFPI in 9 glioblastomas with macroscopic hematoma and 30 glioblastomas without macroscopic hemorrhage. Although TF was expressed in most glioblastomas irrespective of the presence or absence of macroscopic hemorrhage, the staining patterns differed significantly: TF-positive glioma cells were diffusely present in the non-hemorrhage group; in the group with hemorrhage, positive cells, primarily macrophages, were scattered throughout the tissue examined. The expression of TFPI was significantly higher in the group with than in the group without hemorrhage. Our results suggest that local suppression of the TF-dependent coagulation cascade is a contributing factor that permits the occurrence of intratumoral hemorrhage.

Midline exposure of the thoracoabdominal aorta.

Extended aortic replacement from the aortic arch to the descending thoracic or thoracoabdominal aorta has been performed through a left thoracotomy or a thoracoabdominal incision combined with or without a median sternotomy. However, a left thoracotomy incision may be unfavorable when dense adhesion of the lung is anticipated. We report a redo patient who underwent simultaneous replacements of the aortic arch and the thoracoabdominal aorta through a midline incision without entering the left pleural cavity.

Molecular cloning of a novel human protein kinase, kpm, that is homologous to warts/lats, a Drosophila tumor suppressor.

A novel human protein kinase, designated kpm, was identified and molecularly cloned. The isolated cDNA clone had an open reading frame consisting of 1088 amino acid residues with a putative kinase domain located near the carboxy-terminus. Homology search revealed that kpm belongs to a subfamily of serine/threonine protein kinases including warts/lats, a Drosophila tumor suppressor. Among these, kpm is most homologous to, but distinct from, recently reported LATS1, a human homolog of Drosophila warts/lats. Northern blot analysis disclosed that kpm is expressed as a 6.0 kb transcript in most of the tissues examined and also as an additional shorter 4.0 kb transcript in testis. Western blotting using polyclonal rabbit anti-kpm antibody detected kpm protein as a band with an apparent Mr of 150 kD. Immune complex kinase assay of HA-tagged kpm showed that kpm had kinase activity and phosphorylated itself in vitro. Studies with synchronized HeLa cells indicated that kpm protein was expressed relatively constantly throughout the cell cycle and underwent significant phosphorylation at mitotic phase. These results suggest that kpm plays a role in cell cycle progression during mitosis and its deletion or dysfunction might be involved in certain types of human cancers.

Purification and characterization of factor VII inhibitor found in a patient with life threatening bleeding.

We recently observed a patient with acquired inhibitor-induced F.VII deficiency whose plasma level of F.VII was < 1.0%. However, the biochemical nature of the inhibitor has not yet been clarified. In the present study, we purified the F.VII inhibitor from the patient's plasma by using activated F.VII (F.VIIa)-conjugated gel and characterized the inhibitor. The results showed that the inhibitor comprised two kinds of antibodies: one was eluted with EDTA (antibody 1) and the other with glycine-HCl buffer (pH 2.3) (antibody 2) from the F.VIIa affinity gel. SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting analysis of these inhibitors demonstrated that both antibodies had features of immunoglobulin G1 (IgG1) with kappa and lambda-light chains. Antibody 1 bound to the immobilized F.VIIa with a high affinity in the presence of calcium ion, while antibody 2 bound to the F.VIIa very weakly and the binding was independent of calcium ion. Immunoblotting analysis demonstrated that antibody 1 bound to the light chain of F.VIIa after reduction with 2-mercaptoethanol, while it did not react with either the gamma-carboxyglutamic acid (Gla)-domainless light chain of F.VIIa or the heavy chain with the protease domain. Antibody 1 markedly inhibited the activity of tissue factor-F.VIIa complex. Based on these observations, it is suggested that F.VIIa autoantibody (antibody 1) recognizes the calcium-dependent conformation within or near the Gla domain and inhibits F.VIIa activity by interacting with the light chain.

Intravascular free tissue factor pathway inhibitor is inversely correlated with HDL cholesterol and postheparin lipoprotein lipase but proportional to apolipoprotein A-II.

To elucidate the distribution and clinical implications of tissue factor pathway inhibitor (TFPI) concentrations, we measured TFPI levels consisting of preheparin free, lipoprotein-bound (Lp-bound), and endothelial cell-anchor pools in 156 patients with coronary artery disease (average age, 61.2+/-9.1 years; range, 32 to 78 years) by heparin infusion (50 IU/kg) and compared them with the preheparin TFPI levels of 229 healthy subjects (average age, 59. 6+/-9.4 years; range, 41 to 80 years). The patients had lower preheparin free TFPI and lower HDL cholesterol (HDL-C) levels than the healthy subjects with equivalent Lp-bound forms (free TFPI, 15. 9+/-6.5 versus 19.2+/-8.1 ng/mL). In a partial correlation analysis, the preheparin free TFPI levels were shown to be inversely correlated with the HDL-C concentrations in both the patients (r=-0. 454, P<0.001) and the healthy subjects (r=-0.136, P<0.05). As determined by comparison of preheparin and postheparin plasma, the patients generally showed preheparin free TFPI <10%, Lp-bound TFPI at 30%, and endothelial cell-anchor TFPI at 60%. When the patients were divided into 4 categories by their LDL cholesterol (LDL-C, 130 mg/dL) and HDL-C (40 mg/dL) levels to specify their coronary risks, the low-HDL-C groups had significantly increased preheparin and postheparin free TFPI levels and decreased postheparin LPL levels, whereas the high-LDL-C groups showed increased levels of Lp-bound TFPI. In a partial correlation analysis, we found a proportional relation between postheparin free TFPI and apolipoprotein A-II (r=0. 5327) and between HDL-C and LPL (r=0.4906), whereas postheparin free TFPI was inversely correlated with HDL-C (r=-0.4280) and postheparin LPL (r=-0.4791). The inverse relationship between TFPI and LPL suggests that increased free TFPI concentrations as a compensatory response of the endothelium to prevent atherothrombotic processes compete with and displace LPL on endothelial surface, resulting in reduced LPL and low HDL-C.

Monoclonal antibody specific for tissue factor pathway inhibitor-factor Xa complex: its characterization and application to plasmas from patients with disseminated intravascular coagulation and pre-disseminated intravascular coagulation.

Tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor with three tandem inhibitory domains (K1, K2 and K3), inhibits the initial reactions of the extrinsic blood coagulation pathway through its K1 and K2 domains. We prepared and characterized a monoclonal antibody (Mab8-1) against TFPI-factor Xa (TFPI-Xa) complex. The reactivities of Mab8-1 toward TFPI-Xa complex, TFPI without C-terminal (TFPI-C)-Xa complex, K1K2-Xa complex and K2K3-Xa complex were examined using a surface plasmon resonance analysis (Biacore). The Biacore system allowed a quantitative analysis of antibody-antigen interaction, in real time, from which the association and dissociation rate constants could readily be obtained. The bindings of Mab8-1 to TFPI-Xa complex, TFPI-C-Xa complex and K2K3-Xa complex were each concentration-dependent. However, no binding of Mab8-1 to the K1K2-Xa complex was observed. The binding of Mab8-1 to TFPI or Xa was also not observed. These results suggested that the epitope for Mab8-1 was exposed in the K3 domain of TFPI, which was generated by the conformational change after the formation of TFPI-Xa complex. We then developed an enzyme-linked immunosorbent assay method specific for TFPI-Xa complex using Mab8-1, and we used this assay to measure plasma levels of TFPI-Xa. The normal range assessed from analyses of plasma from 30 normal healthy volunteers was 17.7-66.7 with a mean of 35.5 +/- 11.7 pmol/l. In order to asses the clinical implication of TFPI-Xa complex in the plasma of patients with thrombotic disorders, plasma concentrations were measured in 37 patients with disseminated intravascular coagulation (DIC) caused by a variety of underlying diseases. The TFPI-Xa antigen levels were significantly higher in the patients with DIC (51.9 +/- 21.6 pmol/l) and the 36 patients with pre-DIC (55.1 +/- 20.2 pmol/l) than in the 137 non-DIC patients (37.9 +/- 13.1 pmol/l). In the patients with DIC or pre-DIC, there was no significant correlation between TFPI-Xa complex and the elevated levels of thrombin-antithrombin complex, plasmin-alpha2 plasmin inhibitor complex, D-dimer, soluble fibrin monomer, soluble thrombomodulin or tissue factor. These data indicate that the plasma level of TFPI-Xa seems to be a novel independent molecular marker of DIC and pre-DIC.

[A case of mitral valve replacement and left atrial plication for infantile Marfan syndrome with giant left atrium due to mitral valve regurgitation].

In Marfan syndrome, there is a subset, called infantile Marfan syndrome, in which the disease is diagnosed during infancy and cardiac lesions including mitral regurgitation and aortic root dilatation tend to be deteriorated rapidly. In infantile Marfan syndrome, respiratory function is sometimes impaired when skeletal abnormalities such as scoliosis and pectus excavatum are severe. In this report, we describe a 2-year and 4-months old boy with infantile Marfan syndrome who presented with severe mitral regurgitation and the collapsed left lung. In addition to the impairment of respiratory function due to severe scoliosis, the left lung was collapsed because of the compression of the left bronchus by the enlarged left atrium. The patient required mitral valve replacement concomitantly with left atrial plication, resulting in the decompression of the left bronchus and the re-expansion of the left lung. Characteristics and surgical management of infantile Marfan syndrome are discussed in this report.

Adenovirus-mediated local expression of human tissue factor pathway inhibitor eliminates shear stress-induced recurrent thrombosis in the injured carotid artery of the rabbit.

The main cause of acute coronary syndrome may be recurrent thrombosis, which is initiated by the activation of the extrinsic coagulation pathway. Tissue factor (TF) pathway inhibitor (TFPI) efficiently inhibits an early step in this pathway by the formation of a complex with factor VIIa, TF, and factor Xa. We determined whether local TFPI gene transfer can inhibit thrombosis in an injured artery without inducing systemic side effects. Balloon-injured rabbit carotid arteries were infected with an adenoviral vector that expressed either human TFPI (AdCATFPI) or bacterial beta-galactosidase (AdCALacZ). Two to 6 days after gene transfer, thrombosis was induced by the production of constant stenosis of the artery, and blood flow was measured continuously with an electromagnetic flow probe. A cyclic flow variation, which is thought to reflect the recurrent formation and dislodgment of mural thrombi, was observed in all AdCALacZ-infected arteries as well as in saline-infused arteries. In contrast, no cyclic flow variation was detectable in AdCATFPI-transfected arteries, even in the presence of epinephrine (1 microg. kg-1. min-1 infusion). Prothrombin time, activated partial thromboplastin time, and the ex vivo platelet aggregation induced by either adenosine diphosphate or collagen were unaltered in AdCATFPI-infected rabbits. We found that in vivo TFPI gene transfer into an injured artery completely inhibits the recurrent thrombosis induced by shear stress even in the presence of catecholamine, without affecting systemic coagulation status. Adenovirus-mediated local expression of TFPI may have the potential for the treatment of human thrombosis.

Monkey hepatocytes efficiently express tissue factor pathway inhibitor (TFPI), in contrast with human and rat hepatocytes.

It has been reported that tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor that regulates the extrinsic blood coagulation pathway, is not expressed in human, bovine, rabbit, or rat liver. Here, we found that TFPI is efficiently expressed in Macaque monkey liver. Monkey hepatocytes were identified as the expression cells by Northern blot analysis. The hepatocytes were stained with anti-human TFPI antibody, as were endothelial cells of the small vessels. We isolated and sequenced the 5'-flanking 1.4 kb regions of monkey and human TFPI genes, and found them to show 92.6% identity in their nucleotide sequences. We measured their transcriptional activities using a luciferase reporter gene and showed that the activity of the monkey TFPI gene is higher than that of the human gene in monkey primary hepatocytes. Although the binding motif of hepatocyte nuclear factor-1 is present only in the monkey gene, the site does not seem to be involved in the transcriptional activity. Mutagenetic analyses revealed that the region from -138 to +28 in the monkey gene is important for the expression of TFPI in hepatocytes. The present study indicates that the expression of the monkey TFPI gene is regulated by different mechanisms from the human TFPI gene.

Fibrin-rich and platelet-rich thrombus formation on neointima: recombinant tissue factor pathway inhibitor prevents fibrin formation and neointimal development following repeated balloon injury of rabbit aorta.

Thrombus formation and neointimal growth are the critical events in restenosis after balloon angioplasty. However, the responses of diseased vessels to injuries caused by balloon angioplasty have not been well examined. We investigated the thrombus formation and neointimal development following the balloon injury to the previously induced neointima in the rabbit aorta and the effects of recombinant tissue factor pathway inhibitor (rTFPI) on these responses. Rabbit thoracic aortas were subjected to injury with a Fogarty 4F balloon catheter at 1.75 atm (first injury), and 4 weeks later the same vessels were subjected to the second injury with a Swan-Ganz 5F balloon catheter at 1.4 atm (mild-injury group) or 1.8 atm (severe-injury group), and immediately after that a retrograde bolus injection of rTFPI (100 microg/kg body weight) or saline was performed into the injured segments via the central tube of the Swan-Ganz catheter. Twenty minutes after the second injury, the injured surfaces were covered with platelet-rich thrombi in the mild-injury group and with fibrin-rich thrombi in the severe-injury group. Damaged intimal smooth muscle cells, which were immunohistochemically positive for tissue factor (TF), were observed beneath the fibrin-rich thrombi. The neointima 4 weeks after the second injury was significantly thicker in the severe-injury group than in the mild-injury group. The bolus infusion of rTFPI markedly inhibited fibrin formation on the injured surfaces, and significantly reduced the neointimal development in the severe-injury group at 4 weeks after the second injury. These results indicate that TF-dependent coagulation pathway is primarily responsible for fibrin-rich thrombus formation and may play an important role in neointimal development following the balloon injury to the rabbit aortic neointima. Additionally the bolus administration of rTFPI to the injured vessels could prevent mural thrombus formation and neointimal growth after balloon angioplasty.