[Redo Aortic and Mitral Valve Replacement by Manouguian's Procedure for Active Prosthetic Valve Infection].

The damage to the intervalvular fibrous trigone (IVFT) by infective endocarditis makes combined aortic and mitral valve replacement difficult. We performed Manouguian's double valve replacement for such a case and obtained a good result. A 81-year-old male underwent emergency operation due to active prosthetic valve endocarditis. He had a history of receiving combined aortic and mitral valve replacement because of active infective endocarditis at the age of 74 and redo aortic valve replacement 3 years after that. The infectious lesion extended from the mitral annulus to the IVFT and the aortic annulus, and it caused the prosthetic valve detachment from the aortic annulus. Manouguian's double valve replacement was required for radical resection and reconstruction of the IVFT. No recurrent infection or paravalvular leakage was observed during 49months follow up period. Manouguian's procedure is useful for complete resection of the infected IVFT and makes combined aortic and mitral valve replacement safer.

[Second use of preserved aortic cusps for bentall procedure after aortic valve replacement with intravalvular implantation technique in aortitis syndrome].

A 44-year-old woman who had undergone aortic valve replacement with intravalvular implantation technique due to aortitis syndrome 13 years before, required Bentall procedure and hemiarch replacement because of the tissue valve dysfunction and the root and ascending aortic aneurysms. The exposed native aortic cusps sandwiched between the felt pledgets and the tissue valve seemed to be useful in reinforcing the proximal anastomosis of the composite graft. A combination of an intravalvular implantation technique and a skirted composite graft technique was applied, and her postoperative course has been uneventful for more than 2 and a half years.

Impact of polyvascular disease on clinical outcomes in patients undergoing coronary revascularization: an observation from the CREDO-Kyoto Registry Cohort-2.

OBJECTIVE: Patients with coronary artery disease (CAD) often have prior stroke or concomitant extra-cardiac vascular disease (EVD) such as cerebral, aortic, or peripheral vascular disease. However, clinical outcomes after coronary revascularization in patients with polyvascular disease have not been fully elucidated. METHODS: Among 15,263 patients undergoing first coronary revascularization enrolled in the CREDO-Kyoto registry Cohort-2 from January 2005 to December 2007, there were 1443 patients with prior stroke (stroke + CAD group), 974 patients with EVD (EVD + CAD group), 253 patients with both prior stroke and EVD (stroke/EVD/CAD group) and 12,593 patients with neither prior stroke nor EVD (CAD alone group [reference]). RESULTS: The cumulative incidence of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction and stroke) through 3 years was significantly higher in patients with polyvascular disease compared with reference patients (19.9% in the stroke + CAD group, 18.5% in the EVD + CAD group, 20.1% in the stroke/EVD/CAD group, and 11.2% in the CAD alone group, P < 0.0001). After adjusting confounders, the presence of EVD and/or stroke was independently associated with higher risk for MACE compared with the reference group (adjusted HR [95%CI]: 1.34 [1.17-1.54], P < 0.0001 in the stroke + CAD group, 1.56 [1.32-1.84], P < 0.0001 in the EVD + CAD group, and 1.66 [1.24-2.23], P = 0.0007 in the stroke/EVD/CAD group). However, the presence of EVD and/or stroke was not associated with higher risk for myocardial infarction. CONCLUSIONS: Clinical outcome after coronary revascularization was worse in patients with prior stroke and/or EVD, which was mainly driven by the increased risk for non-coronary cardiovascular events.

Clinical evidence versus patients' perception of coronary revascularization.

Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) have been developed as revascularization techniques for coronary artery disease. CABG offers a survival advantage over medical therapy, especially for high-risk coronary patients, whereas PCI is the most frequent initial procedure to treat multi-vessel coronary artery disease, because it is less invasive. However, PCI has been found to confer no additional benefit with respect to myocardial infarction (MI) or death. The SYNTAX trial compared the outcomes of patients with left main and/or three-vessel coronary artery disease treated with CABG versus PCI using drug-eluting stents. The 4-year results showed that all-cause mortality and cardiac death were both significantly higher in the PCI group than in the CABG group. Despite extensive evidence of the advantages of CABG over PCI with respect to death or MI, PCI is recommended more often and CABG less often than indicated in the guidelines. Patients with coronary artery disease should receive unbiased information about the risks and benefits of each procedure and the alternatives. A multidisciplinary approach, referred to as "the Heart Team", could help to improve the informed consent process when recommending revascularization treatment for coronary artery disease.

Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury.

Much attention is currently focused on the role of perivascular adipose tissue in development of cardiovascular disease (CVD). Some researchers view it as promoting CVD through secretion of cytokines and growth factors called adipokines, while recent reports reveal that perivascular adipose tissue can exert a protective effect on CVD development. Furthermore, adiponectin, an anti-inflammatory adipokine, reportedly suppresses neointimal hyperplasia after endovascular injury, whereas such vascular remodeling is enhanced by pro-inflammatory adipokines secreted by perivascular adipose, such as tumor necrosis factor-α (TNF-α). These findings suggest that extent of vascular remodeling, a pathological process associated with CVD development, depends on the balance between pro- and anti-inflammatory adipokines secreted from perivascular adipose tissue. We previously demonstrated that angiopoietin-like protein 2 (Angptl2), a pro-inflammatory factor secreted by adipose tissue, promotes adipose tissue inflammation and subsequent systemic insulin resistance in obesity. Here, we examined whether Angptl2 secreted by perivascular adipose tissue contributes to vascular remodeling after endovascular injury in studies of transgenic mice expressing Angptl2 in adipose tissue (aP2-Angptl2 transgenic mice) and Angptl2 knockout mice (Angptl2(-/-) mice). To assess the role of Angptl2 secreted by perivascular adipose tissue on vascular remodeling after endovascular injury, we performed adipose tissue transplantation experiments using these mice. Wild-type mice with perivascular adipose tissue derived from aP2-Angptl2 mice exhibited accelerated neointimal hyperplasia after endovascular injury compared to wild-type mice transplanted with wild-type tissue. Conversely, vascular inflammation and neointimal hyperplasia after endovascular injury were significantly attenuated in wild-type mice transplanted with Angptl2(-/-) mouse-derived perivascular adipose tissue compared to wild-type mice transplanted with wild-type tissue. RT-PCR analysis revealed that mouse Angptl2 expression in perivascular adipose tissue was significantly increased by aging, hypercholesterolemia, and endovascular injury, all risk factors for coronary heart disease (CHD). Immunohistochemical and RT-PCR analysis of tissues from patients with CHD and from non-CHD patients indicated that ANGPTL2 expression in epicardial adipose tissue was unchanged. Interestingly, that analysis also revealed a positive correlation in ANGPTL2 and ADIPONECTIN expression in epicardial adipose tissue of non-CHD patients, a correlation not seen in CHD patients. However, in epicardial adipose tissue from CHD patients, ANGPTL2 expression was positively correlated with that of TNF-α, a correlation was not seen in non-CHD patients. These findings suggest that pro-inflammatory adipokines cooperatively accelerate CHD development and that maintaining a balance between pro- and anti-inflammatory adipokines likely protects non-CHD patients from developing CHD. Overall, our studies demonstrate that perivascular adipose tissue-secreted Angptl2 accelerates vascular inflammation and the subsequent CVD development.

Macrophage-derived angiopoietin-like protein 2 accelerates development of abdominal aortic aneurysm.

OBJECTIVE: Recently, we reported that angiopoietin-like protein 2 (Angptl2) functions in various chronic inflammatory diseases. In the present study, we asked whether Angptl2 and its associated chronic inflammation contribute to abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Immunohistochemistry revealed that Angptl2 is abundantly expressed in infiltrating macrophages within the vessel wall of patients with AAA and in a CaCl(2)-induced AAA mouse model. When Angptl2-deficient mice were used in the mouse model, they showed decreased AAA development compared with wild-type mice, as evidenced by reduction in aneurysmal size, less severe destruction of vessel structure, and lower expression of proinflammatory cytokines and matrix metalloproteinase-9. However, no difference in the number of infiltrating macrophages within the aortic aneurysmal vessel wall was observed between genotypes. AAA development was also significantly suppressed in wild-type mice that underwent Angptl2-deficient bone marrow transplantation. Expression levels of proinflammatory cytokines and metalloproteinase-9 in Angptl2-deficient macrophages were significantly decreased, and those decreases were rescued by treatment of Angptl2 deficient macrophages with exogenous Angptl2. CONCLUSIONS: Macrophage-derived Angptl2 contributes to AAA development by inducing inflammation and degradation of extracellular matrix in the vessel wall, suggesting that targeting the Angptl2-induced inflammatory axis in macrophages could represent a new strategy for AAA therapy.

Intravascular papillary endothelial hyperplasia in an aneurysm of the superficial temporal artery: Report of a case.

We herein report a rare case of an intravascular papillary endothelial hyperplasia in an aneurysm of the superficial temporal artery. The patient was a 67-year old Japanese woman. She noticed a throbbing swelling in her left forehead, which had gradually been increasing in size. She had no previous history of head trauma. Ultrasonography and three-dimensional computed tomographic angiography revealed an aneurysm with a mural thrombus measuring 10 mm in diameter fed by the frontal branch of the left superficial temporal artery. The aneurysm of the superficial temporal artery was dissected from the surrounding tissues, and was resected after ligation of feeding vessels. A microscopic examination revealed papillary endothelial hyperplasia in a true aneurysm. Nontraumatic aneurysms of the superficial temporal artery are rare. In the previous English literature, there have only been a few reports of papillary endothelial hyperplasia in an artery, and none in an aneurysm of the superficial temporal artery.

Nifedipine increases energy expenditure by increasing PGC-1α expression in skeletal muscle.

Nifedipine, an L-type calcium (Ca) channel blocker, is one of the most widely used Ca channel-blocking medications for hypertension. Previous studies have reported an association of nifedipine hypertensive treatment with decreased body weight in obese hypertensive humans and rat models. However, the precise mechanism underlying how nifedipine functions metabolically has not been elucidated. Here, we investigated the long-term effect of a non-hypotensive nifedipine dose using a mildly obese, endothelial NO synthase-deficient mouse model. Treating these mice with nifedipine decreased their body weight gain ratio, and white adipose tissue weight compared with the untreated controls. Metabolic analyses indicated that nifedipine treatment upregulated whole-body energy expenditure through increasing oxygen consumption and reducing the respiratory exchange ratio, suggesting that nifedipine promotes lipid oxidation rather than carbohydrate utilization. Furthermore, nifedipine treatment upregulated the expression of the peroxisome proliferator-activated receptor-γ coactivator -1α (PGC-1α) in skeletal muscle. Overall, these results suggest that a non-hypotensive dose of nifedipine has pleiotropic effects on energy expenditure that could ameliorate obesity.

Debate over patient-centered care: percutaneous coronary intervention or coronary artery bypass grafting?

Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) have developed as effective therapies to treat coronary artery disease. Initial CABG is associated with lower mortality than initial medical management, especially among high- and intermediate-risk patients with coronary artery disease. However, PCI is currently the most frequent initial treatment delivered by interventional cardiologists to treat multivessel coronary artery disease, despite substantial evidence from meta-analyses of randomized trials and registry data favoring CABG. Recent advancements in PCI did not result in detectable improvements in death or myocardial infarction compared with medical therapy, although significant reductions in target lesions or vessel revascularization were identified after implantation of a drug-eluting stent (DES) rather than a bare-metal stent. The SYNTAX trial compared patients with left main and/or three-vessel coronary artery disease treated with DES or CABG. The results of the trial demonstrated the 1-year inferiority of PCI compared with CABG with respect to major adverse cardiac and cerebrovascular events. Nevertheless, patients with coronary artery disease continue to receive more recommendations for PCI and fewer for CABG than are indicated in the guidelines. A multidisciplinary team approach should be the standard of care when recommending interventions for treating complex coronary artery disease among patients for whom CABG is superior in terms of survival and freedom from reintervention.

The value of angiogenic therapy with intramyocardial administration of basic fibroblast growth factor to treat severe coronary artery disease.

BACKGROUND: Basic fibroblast growth factor (bFGF) was administered intramyocardially together with CABG to induce myocardial neovascularizaton and collateral growth in patients with ungraftable coronary arteries. Coronary angiographic and myocardial scintigraphic findings revealed that the effects of CABG were potentially confounding. METHODS AND RESULTS: Patients in the bFGF group (n = 16) underwent angiogenic therapy using bFGF for ungraftable territory, and incomplete revascularization (IR) patients (n = 22) underwent only CABG. The magnitude of collateral development was assessed by the Rentrop score and collateral connection (CC) grade. Rentrop scores tended to increase among patients in the bFGF group (before vs. after surgery, 1.9 ± 1.2 vs. 2.3 ± 1.2, p = 0.05), but not in the IR group. The CC grade significantly increased among patients in the bFGF group (before vs. after surgery, 1.0 ± 0.9 vs. 1.4 ± 0.5, p <0.05), but not in the IR group. Myocardial perfusion in territories injected with bFGF improved in 13 patients (81%) of the bFGF group, and also in the nonbypassed territory in 4 IR patients (25%) (p <0.05). CONCLUSION: Angiogenic therapy with bFGF induced collateral development and improved myocardial perfusion in territories injected with bFGF.

Different roles of Foxo1 and Foxo3 in the control of endothelial cell morphology.

Foxo1, a member of the Foxo subfamily of forkhead box transcription factors, is known to be essential for progression of normal vascular development in the mouse embryos. In the cultures of endothelial cells derived from embryonic stem cells, Foxo1-deficient endothelial cells exhibit an abnormal morphological response to vascular endothelial growth factor-A (VEGF-A), which is characterized by a lack of cell elongation, yet the molecular mechanisms governing endothelial cell morphology under angiogenic stimulation remain unknown. Here, we report that transforming growth actor-beta also induces endothelial cell elongation in collaboration with Foxo1 and VEGF-A. Furthermore, tetracycline-regulated induction of Foxo3, another member of the Foxo subfamily, into Foxo1-null endothelial cells failed to restore abnormal morphological response to VEGF-A at an early differentiation stage. In contrast, Foxo1 and Foxo3 exerted the same function at a late differentiation stage, i.e. enhancement of VEGF responsiveness and promotion of cell elongation. Our results provide evidence that endothelial cell morphology is regulated by several mechanisms in which Foxo1 and Foxo3 express distinct functional properties depending on differentiation stages.

Therapeutic angiogenesis with autologous hepatic tissue implantation and omental wrapping.

BACKGROUND: The liver produces various angiogenic and cytoprotective growth factors and the omentum has potent angiogenic properties that promote wound healing. The ability of hepatic tissue implantation plus omental wrapping to induce angiogenesis and restore cardiac function was investigated in a rat model of infarction. METHODS AND RESULTS: Myocardial infarction was induced in rats using coronary artery ligation. The omentum was wrapped (omentopexy group), hepatic tissue implantation was combined with omental wrapping (hepatic tissue implantation (H) group) or no other treatment was applied (control (C) group), and then ventricular function was evaluated by echocardiography 4 weeks later. Infarct size, ventricular remodeling, vascular density and collagen density were morphometrically and histologically evaluated. The expression of angiogenic growth factors in implanted tissues was examined using RT-PCR. The H group had thicker (p<0.05) and less expanded infarcts (p<0.001), as well as higher capillary (p<0.01) and arteriolar (p<0.05) density in the infarct border zone, than the C group. Hepatocyte growth factor was obviously expressed and the expression of both basic fibroblast growth factor and vascular endothelial growth factor was increased in the H group. CONCLUSIONS: Hepatic tissue implantation combined with omental wrapping stimulated angiogenesis, attenuated left ventricular remodeling and improved cardiac function.

Overlapping roles of the methylated DNA-binding protein MBD1 and polycomb group proteins in transcriptional repression of HOXA genes and heterochromatin foci formation.

Methylated DNA binding domain (MBD) proteins and Polycomb group (PcG) proteins maintain epigenetic silencing of transcriptional activity. We report that the DNA methylation-mediated repressor MBD1 interacts with Ring1b and hPc2, the major components of Polycomb repressive complex 1. The cysteine-rich CXXC domains of MBD1 bound to Ring1b and the chromodomain of hPc2. Chromatin immunoprecipitation analysis revealed that MBD1 and hPc2 were present in silenced Homeobox A (HOXA) genes which could be reactivated by knockdown of either MBD1 or hPc2, suggesting that MBD1 and hPc2 cooperate for transcriptional repression of HOXA genes. In the nuclei of HeLa cells, MBD1 existed in close association with these PcG proteins in some heterochromatin foci, whereas an MBD1 mutant lacking the CXXC domains or an hPc2 mutant lacking the chromodomain lost this colocalization in foci. Use of the DNA demethylating agent 5-azadeoxycytidine abolished the formation of MBD1 foci but not PcG foci. Knockdown of MBD1 by small interfering RNAs did not affect the foci containing hPc2 and Ring1b, whereas the MBD1 foci were not influenced by knockdown of hPc2. These indicate that the heterochromatin foci showing MBD1 and hPc2 colocalization arise through the interaction of MBD1 and hPc2 and that the foci of MBD1 are separable from those of the PcG proteins per se. Our present findings suggest that MBD1 and PcG proteins have overlapping roles in epigenetic gene silencing and heterochromatin foci formation through their interactions.

Prognostic factors of curatively resected esophageal carcinoma associated with multiple metastatic lymph nodes.

BACKGROUND/AIMS: Prognosis of esophageal carcinoma with multiple metastatic lymph nodes is dismal despite radical operation and adjuvant therapy. We investigated prognostic factors for curatively resected esophageal carcinoma with multiple positive nodes. METHODOLOGY: From January 1983 to December 2002, 343 patients with thoracic esophageal carcinoma underwent an esophagectomy with curative intent. Of these patients, 82 patients were associated with 4 or more histopathologically positive nodes. Of these patients, 59 patients underwent a curative resection. Of these 59 patients, 7 patients who died of postoperative complications during the hospital stay were excluded. Therefore, 52 patients were enrolled in this study. Survival curves were compared after stratifications according to 14 clinicopathologic variables. Independent prognostic factors were detected using a multivariate Cox proportional hazard model. RESULTS: The cumulative 5-year survival rate for the subjects was 10.6%. The factors affecting cumulative survival rate by a univariate analysis were intramural metastasis (absence vs. presence) (p=0.03), and postoperative therapy (performed vs. not performed) (p=0.02). A multivariate analysis detected the performance of postoperative therapy (Hazard Ratio= 0.390, p= 0.002) and the absence of intramural metastasis (Hazard ratio=0.429, p=0.01) as positive prognostic factors. CONCLUSIONS: The positive prognostic factors for esophageal carcinoma with multiple lymph node metastases were the absence of intramural metastasis and the performance of adjuvant therapy.

Inhibition of DNA binding of Sox2 by the SUMO conjugation.

Sox2 is a member of the high mobility group (HMG) domain DNA-binding proteins for transcriptional control and chromatin architecture. The HMG domain of Sox2 binds the DNA to facilitate transactivation by the cooperative transcription factors such as Oct3/4. We report that mouse Sox2 is modified by SUMO at lysine 247. Substitution of the target lysine to arginine lost the sumoylation but little affected transcriptional potential or nuclear localization of Sox2. By contrast with the unmodified form, Sox2 fused to SUMO-1 did not augment transcription via the Fgf4 enhancer in the presence of Oct3/4. Further, SUMO-1-conjugated Sox2 at the lysine 247 or at the carboxyl terminus reduced the binding to the Fgf4 enhancer. These indicate that Sox2 sumoylation negatively regulates its transcriptional role through impairing the DNA binding.

Effects of intramyocardial administration of slow-release basic fibroblast growth factor on angiogenesis and ventricular remodeling in a rat infarct model.

BACKGROUND: Basic fibroblast growth factor (bFGF) stimulates neoangiogenesis. Incorporation into biodegradable gelatin hydrogels provides the sustained release of bFGF. The effects of intramyocardial injections of slow-release bFGF on neoangiogenesis in a rat model of infarction were investigated. METHODS AND RESULTS: Myocardial infarction was induced in rats using coronary artery ligation. A total of 124 rats received an intramyocardial injection of 20 microg of bFGF, the same amount of bFGF incorporated into gelatin hydrogel (bFGF + gel), gelatin hydrogel (gel) or saline. Ventricular function was evaluated by echocardiography 2 or 4 weeks later. Morphometric and histological analyses were used to evaluate infarct size, vascular density and myocardial apoptosis. Capillary density in the infarct border zone was higher in the bFGF and bFGF + gel groups than in the saline and gel groups at 4 weeks (p<0.001). Arteriolar density was higher in the bFGF + gel group than in the other 3 groups (p<0.05). The bFGF and bFGF + gel groups contained fewer apoptotic cardiomyocytes in the border zone than the saline and gel groups (p<0.01). The bFGF+gel group had thicker (p<0.05) and less expanded infarcts (p<0.01) compared with the saline group at 4 weeks. CONCLUSIONS: Incorporation of bFGF in gelatin hydrogels enhanced the effects of bFGF on arteriogenesis, ventricular remodeling and cardiac function.

Onset of liver metastasis after histologically curative resection of pancreatic cancer.

PURPOSE: We assessed the possibility of predicting the time of onset of liver metastases by measuring the postoperative changes in serum carbohydrate antigen (CA)19-9 after curative resection of pancreatic cancers. METHODS: Among 28 patients who underwent histologically defined curative resection of pancreatic cancer between 1984 and 1999, liver metastasis developed in 11 patients with elevated serum CA19-9 levels. We plotted the serum CA19-9 levels against time on a semilogarithmic graph. Over the linear part of the curve, the time when log[CA19-9] equaled zero was defined as the time of onset of liver metastases. The log[CA19-9] level doubling time was then calculated and evaluated in relation to the survival period. RESULTS: The serum CA19-9 levels increased linearly in 10 of the 11 patients. The predicted time of onset of liver metastasis ranged from preoperative day 163.0 to postoperative day 27.1, being preoperative in eight patients. The doubling time until death correlated strongly with survival in the eight patients with maintained log[CA19-9] linearity. CONCLUSION: The onset of liver metastases might be preoperative in patients with advanced pancreatic cancer. Therefore, neoadjuvant chemotherapy should be mandatory even if there is no sign of liver metastases.