伊東 昌広

BackgroundHepatocyte transplantation (HTx) has yielded significant improvements in liver function and survival in experimentally induced acute liver failure and liver-based metabolic disease. However, transplantation is inefficient, and it is thought that transplanted hepatocytes have a shortened lifespan because of inflammation involving excess nitric oxide (NO). The present study aimed to clarify whether edaravone, a free radical scavenger used to treat ischemic stroke, could reduce ischemic changes in hepatocyte-transplanted livers. MethodsEdaravone (3mg/kg) was administered intravenously 24h before HTx to Nagase analbuminemic rats (NARs). Hepatocytes were isolated, and 30 x 10(6) cells were injected in a 1.0-ml volume directly into the spleens of NARs. All experimental groups studied received FK506 to control rejection. Animals in Group A received medium-only; Group B received HTx only; and Group C received HTx and edaravone. Forty-eight hours after transplantation, the hepatocytes from animals were isolated and analyzed for staining with propidium iodide- and annexin-V using flow cytometry. Liver sections were also studied by immunostaining for albumin, and TUNEL. Peripheral blood serum albumin levels were measured on post-transplant days 0, 3, 5, 7, 10 and 14 using ELISA. ResultsThe edaravone-treated animals demonstrated an increased number of engrafted donor hepatocytes in the liver. The edaravone-treated liver sections also contained fewer TUNEL-positive cells and animals that received edaravone had higher serum albumin levels post-transplantation. Hepatocytes were also found to have increased in numbers 2 weeks following treatment with edaravone. ConclusionsEdaravone administration during HTx can suppress apoptosis near the transplanted cells, increasing engraftment. These studies indicate its potential usefulness for future clinical application.

Mechanical alternans (MA) is frequently observed in patients with heart failure, and is a predictor of cardiac events. However, there have been controversies regarding the conditions and mechanisms of MA. To clarify heart rate-dependent contractile properties related to MA, we performed incremental right atrial pacing in 17 idiopathic dilated cardiomyopathy (DCM) patients and in six control patients. The maximal increase in left ventricular dP/dt during pacing-induced tachycardia was assessed as the force gain in the force-frequency relationship (FG-FFR), and the maximal increase in left ventricular dP/dt of the first post-pacing beats was examined as the force gain in poststimulation potentiation (FG-PSP). As a result, MA was induced in 9 DCM patients (DCM MA(+)) but not in the other 8 DCM patients (DCM MA(-)), and not in any of the control patients. DCM MA(+) had significantly lower FG-FFR (34.7 ± 40.9 vs 159.4 ± 103.9 mmHg/s, P = 0.0091) and higher FG-PSP (500.0 ± 96.8 vs 321.9 ± 94.9 mmHg/s, P = 0.0017), and accordingly a wider gap between FG-PSP and FG-FFR (465.3 ± 119.4 vs 162.5 ± 123.6 mmHg/s, P = 0.0001) than DCM MA(-) patients. These characteristics of DCM MA(+) showed clear contrasts to those of the control patients. In conclusion, MA is caused with an impaired force-frequency relationship despite significant poststimulation potentiation, suggesting that MA reflects ineffective utilization of the potentiated intrinsic force during tachycardia.

We investigated whether correlations between mRNA levels of cytokines versus other proteins from patchy lesion could estimate cytokine paracrine signaling in vivo. Experiments with rat experimental autoimmune myocarditis (EAM), a patchy myocarditis model, indicated IL-1 and other protein levels were correlated, indicating paracrine signaling pathways in vivo. (C) 2012 Elsevier Ltd. All rights reserved.

There have been only a few reports regarding the relation between snow shoveling and acute heart failure syndromes (AHFS). We present a case series of 5 patients who presented with AHFS, all within 5 days after shoveling snow. Although all patients underwent examination at a regular out-patient clinic, no patient had prior signs or symptoms of heart failure. The condition of all patients had gradually deteriorated, with no abrupt onset of dyspnea after shoveling snow. Four of the 5 patients demonstrated a preserved ejection fraction on echocardiography. Snow shoveling may lead to AHFS in patients who are at risk for developing heart failure. (Int Heart J 2012; 53: 394-395)

Laparoscopic gastrointestinal surgery with lymphadenectomy is rarely performed for multiple gastrointestinal cancers. We report four patients undergoing laparoscopic surgery for synchronous cancer of the stomach and colon. Resection of each organ with lymphadenectomy was performed by each specialist and the region of the lymphadenectomy was determined according to the lesion of cancer and its depth. The selection of gastric anastomosis, whether intracorporeal or extracorporeal, depended on the resecting areas of the large bowel to allow a small incision. All four cases were male with the median age of 69 (range 59-77) years. The median number of trocars used were 6 (range 5-8) and median length of incision was 4.5cm (range 4-4.5cm). The median operative time and blood loss were 495.5 minutes (range 390-605) and 88g (range 36-245), respectively. In all four cases, laparoscopic surgery with a lymphadenectomy on each region was successfully accomplished according to the respective progression stage. Anastomosis was completed with a small incision by using techniques and devices to provide a variation of anastomosis methods and incision positions. Laparoscopic surgery with lymphadenectomy was also undertaken for a patient with gastric remnant cancer and colorectal cancer. The median length of the postoperative hospital stay was 14.5 days (range 12-29). No complications were observed after the surgery. There was no case of recurrence during a median follow-up of 84.3 months (range 54.9-111.5). Laparoscopic surgery was feasible for patients with double cancer of the stomach and colon.

The clinical implications of mechanical alternans in patients with pulmonary arterial hypertension (PAH) remain unknown. In this study, the prevalence, characteristics, and prognostic implications of mechanical alternans in patients with PAH were investigated. Thirty-two consecutive patients with PAH confirmed by cardiac catheterization from 2000 to 2010 were included in this cohort study. During cardiac catheterization, 8 patients (25%) showed mechanical alternans at rest. All alternans were detected in the right ventricle and pulmonary trunk. Serum level of brain natriuretic peptide (584 +/- 177 vs 238 +/- 252 pg/ml, p = 0.001), World Health Organization functional class (3.5 +/- 0.5 vs 2.9 +/- 0.4, p = 0.02), mean pulmonary arterial pressure (59 +/- 10 vs 47 +/- 18 mm Hg, p = 0.03), mean right atrial pressure (10 +/- 4 vs 5 +/- 4 ram Hg, p = 0.01), right ventricular end-diastolic pressure (15 +/- 5 vs 9 +/- 5 mm Hg, p = 0.01), and heart rate at catheterization (96 +/- 17 vs 70 +/- 11 beats/min, p = 0.003) were significantly higher in patients with alternans than in those without. Twelve-month mortality of patients with alternans was higher than in patients without alternans (p = 0.03): the 12-month survival rate after cardiac catheterization was 37% for the alternans group and 75% for the group without alternans. In conclusion, isolated right-sided mechanical alternans is not an uncommon event in patients with PAH. The existence of alternans is associated with the severity of PAH and right ventricular dysfunction and implies a poor prognosis in the short term. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:428-431)

Background: Subarachnoid haemorrhage (SAH) is known as one of the aetiologies of out-of-hospital cardiac arrest (OHCA). However, the mechanisms of circulatory collapse in these patients have remained unclear. Methods and results: We examined 244 consecutive OHCA patients transferred to our emergency department. Head computed tomography was performed on all patients and revealed the existence of SAH in 14 patients (5.9%, 10 females). Among these, sudden collapse was witnessed in 7 patients (50%). On their initial cardiac rhythm, all 14 patients showed asystole or pulseless electrical activity, but no ventricular fibrillation (VF). Return of spontaneous circulation (ROSC) was obtained in 10 of the 14 patients (14.9% of all ROSC patients) although all resuscitated patients died later. The ROSC rate in patients with SAH (71%) was significantly higher than that of patients with either other types of intracranial haemorrhage (25%, n = 2/8) or presumed cardiovascular aetiologies (22%, n = 23/101) (p < 0.01). On electrocardiograms, ST-T abnormalities and/or QT prolongation were found in all 10 resuscitated patients. Despite their electrocardiographic abnormalities, only 3 patients showed echocardiographic abnormalities. Conclusions: The frequency of SAH in patients with all causes of OHCA was about 6%, and in resuscitated patients was about 15%. The initial cardiac rhythm revealed no VF even though half had a witnessed arrest. A high ROSC rate was observed in patients with SAH, although none survived to hospital discharge. (C) 2011 Published by Elsevier Ireland Ltd.

Background/Aims: Intraductal papillary mucinous neoplasm (IPMN) and pancreatic endocrine tumors can develop at multiple sites of the pancreas at the same time, sometimes necessitating total pancreatectomy. When low-grade pancreatic malignancy is treated surgically, preservation of function to improve long-term QOL is emphasized. For low grade malignancy tumor of the pancreatic head and tail, we performed middle- segment-preserving pancreatectomy (MSPP), with resection of the pancreatic head and tail alone, resulting in favorable QOL. Methodology: MSPP was performed for 4 patients. Intraoperative blood loss, hospital stay, postoperative complications, histopathological findings and prognosis were examined. Results: Mean intraoperative blood loss was 1255 +/- 365g, mean hospital stay 61 +/- 53 days, and mortality 0%. Postoperatively, pancreatic fistula was observed in 3 patients, but subsided with conservative treatment. In one patient with diabetes preoperatively, diabetes was exacerbated postoperatively, necessitating insulin treatment. No postoperative onset of diabetes was observed. Percent change in body weight during the postoperative 6 month period from preoperative weight was 93 +/- 6.3%. One patient died of malignant lymphoma 1 year and 4 months after surgery. The other patients are alive and socially active. Conclusion: MSPP enables maintenance of good QOL long after surgery for malignancy affecting the head and tail of the pancreas.

Xanthogranulomatous cholecystitis (XGC) is comparatively rare and difficult to distinguish from advanced gallbladder cancer (GBC) by imaging studies. It is important to accurately diagnose XGC preop-eratively, because patients undergo unnecessarily extensive surgery, such as liver resection, if GBC is diagnosed. We selected 3 cases of XGC diagnosed by post-operative pathological examination, between April 2007 and March 2009. Multi Detector-row CT (MD-CT) was useful for preoperative diagnosis of XGC, because it could detect an enhanced continuous mucosal line and intramural hypoattenuated nodule that are distinctive of XGC. Furthermore, measurement of gallbladder wall blood flow (GWBF) and both resistance index (RI) and pulsatility index (PI), indicating vascular resistance by color Doppler US, were also useful for making a differential diagnosis between XGC and GBC. However, it is still difficult to precisely diagnose XGC preoperatively despite progress in imaging studies, and because a higher percentage of XGC coexists with GBC. Therefore intraoperative pathological examination plays an important role in selecting the most suitable surgical procedure. © 2011 The Japanese Society of Gastroenterological Surgery.

Introduction: There is increasing evidence to support a link between inflammation and atrial fibrillation (AF). However, the role of inflammation on new-onset AF is still to be elucidated. Methods: Rats underwent induction of experimental autoimmune myocarditis (EAM). Atrial structural change was evaluated by echocardiography and histological analysis. Electrophysiological data and the in vivo atrial response to burst atrial pacing were evaluated in the acute (2 weeks after EAM induction) and chronic phases (8 weeks after induction). In addition, atrial pacing after 2, 4, and 6 h after lipopolysaccharide (LPS) infusion, when the expression of gap junctions was modified, were challenged with young healthy rats. Results: AF was induced in 11 of 15 chronic phase EAM rats but not in either acute phase EAM rats or LPS infusion rats (P&lt .01). Echocardiography showed dilatation of both atrium and ventricle and a decrease in the ejection fraction in the chronic phase. Histology revealed severe inflammatory lesions only in the acute phase. Interstitial atrial fibrosis as well as the area of atrial myocyte increased in the chronic phase but not in the acute phase. Conclusions: AF could be induced in the chronic phase of myocarditis rats, but not in the acute phase of myocarditis rats or in rats with LPS infusion. Acute inflammation per se did not increase the occurrence of AF induction. Atrial structural remodeling caused by inflammation and hemodynamic effects is necessary to induce AF. © 2010 Elsevier Inc. All rights reserved.

We describe a 36-year-old woman with inverted Takotsubo cardiomyopathy caused by pheochromocytoma crisis. In the acute phase, her electrocardiogram showed ST segment depression in lead II, III, aVF and V2 through V5. On day 14, tall upright T-waves were observed in leads V2 through V5 despite heart failure and basal to midventricular ballooning improved on day 4, and all electrocardiographic abnormalities finally normalized after surgical removal of the pheochromocytomas. This is the first report of electrocardiographic course of inverted Takotsubo cardiomyopathy, and these findings seem as if the inverted electrocardiographic findings are contrary to those of apical ballooning. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Background: Most patients with Takotsubo cardiomyopathy show a favorable outcome. Although several complications have been reported, the frequency of thromboembolism has not been clarified. Methods: Clinical characteristics and complications of 21 consecutive patients (18 female, aged 72 years) with Takotsubo cardiomyopathy during the past 9 years were investigated. Results: The most major complication was heart failure (52%). Thromboembolism was found in 3 patients (14%) and this was the second most frequent cardiovascular complication. One of the 3 patients showed left ventricular thrombus and the other 2 experienced cardioembolic stroke. All 3 patients visited the emergency department more than 48 h after initial chest pain occurred. Conclusions: This study indicates that thromboembolism is a common complication in the acute phase of Takotsubo cardiomyopathy, and anticoagulation therapy should be performed in all patients until wall motion abnormalities improve. Takotsubo cardiomyopathy should be considered one of the important causes of cardioembolic stroke. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

The effect of carperitide, recombinant human atrial natriuretic peptide, on chronic heart failure (HE) has not been clarified. We investigated the beneficial effects of chronic carperitide treatment in rats with HE after experimental autoimmune myocarditis. A 28-day infusion of carperitide (n = 14) or vehicle (n = 14) was administrated to the rats 4 weeks after experimental autoimmune myocarditis induction. After 4 weeks, the myocardial levels of cyclic guanosine monophosphate (cGMP), left ventricular function, myocyte hypertrophy, interstitial fibrosis, myocardial capillary vessel density, and activity of one prominent substrate of cGMP, vasodilator-stimulated phosphoprotein (VASP) that may enhance angiogenesis, were measured. Carperitide treatment increased the myocardial levels of cGMP and attenuated the functional severity along with a decreased myocyte cross-sectional area, interstitial fibrosis, and an increased capillary to myocyte ratio. Furthermore, carperitide treatment enhanced the phosphorylation of VASP at Set-239, which was preferentially phosphorylated by cGMP-dependent protein kinase but not Ser157, which was preferentially phosphorylated by cyclic adenosine monophosphate-dependent protein kinase. Long-term carperitide treatment attenuates ventricular remodeling and ameliorates the progression of chronic FIE The effects of carperitide treatment are associated with increased neovascularization among the residual myocytes and an increase of VASP activation.

Hepatocyte transplantation is a promising treatment for several liver diseases and can also be used as a "bridge" to liver transplantation in cases of liver failure. Although the first animal experiments with this technique began in 1967, it was first applied in humans only in 1992. Unfortunately, unequivocal evidence of transplanted human hepatocyte function has been obtained in only one patient with Crigler-Najjar syndrome type I and, even then, the amount of bilirubin-UDP-glucuronosyltransferase enzyme activity derived from the transplanted cells was not sufficient to eliminate the patient's eventual need for organ transplantation. A literature review was carried out using MEDLINE and library searches. This review considers the following: (1) alternatives or bridges to orthotopic liver transplantation (OLT); (2) solutions to the shortage of organs-the shortage of organ donors has impeded the development of human hepatocyte transplantation, and immortalized hepatocytes in particular could provide an unlimited supply of transplantable cells in a nearly future; (3) future directions. We review these efforts along with hepatocyte transplantation over the last 13 years.

Pancreatic islet transplantation has become one of the ideal treatments for patients with type 1 diabetes mellitus due to improvements in isolation techniques and immunosuppression regimens. In order to ensure the safety and rights of patients, isolated islets need to meet the criteria for regulation as both a biological product and a drug product. For the constant success of transplantation, therefore, all investigators involved in clinical islet transplantation must strive to ensure the safety, purity, and potency of islets in all the phases of clinical islet isolation and transplantation. In this review, we summarize the quality control for clinical islet isolation and transplantation, and the latest topics of pre-transplant islet assessment.

Pheochromocytoma occasionally can lead to left ventricular dysfunction, which is known to be transient. Here, we described a patient showing irreversible dilated cardiomyopathy after surgical resection of pheochromocytomas associated with von Hippel-Lindau disease. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

The differential effects between olmesartan (OM), an angiotensin 2 type 1 receptor blocker (ARB), and azelnidipine (AZ), a calcium channel blocker (CCB), on atrial structural remodeling were studied in spontaneously hypertensive rats (SHR). Eight weeks after treatment, both OM and AZ decreased systolic blood pressure to similar levels. Histological analysis revealed that both OM and AZ had decreased the size of the atrial myocytes and interstitial fibrosis in the atrium, and that the effects of OM were greater than those of AZ. These beneficial effects of OM were associated with less atrial oxidative stress, as assessed by 3-nitrotyrosine staining, and less activation of Rac1, a regulatory component in NADPH oxidase. These results suggest that the ARB was more effective than the CCB in ameliorating atrial structural remodeling due to the suppression of oxidative stress. Copyright (C) 2009 S. Karger AG, Basel

Cardiomyocytes with myocarditis compared with the normal state are thought to change the expressions of various genes greatly, some of which may be new biomarkers or new biologic medicinal products. However, until now, little comprehensive analysis has been made of gene-expression changes in cardiomyocytes with myocarditis. In this study, we performed a DNA microarray analysis by using cardiomyocytes from rat experimental autoimmune myocarditis (EAM). On day 0, rats were immunized with porcine cardiac myosin and cardiomyocytes were isolated and purified from EAM hearts and normal hearts by a method that is hardly thought to change gene expressions in cardiomyocytes. RNA from normal cardiomyocytes and cardiomyocytes of EAM on day 18 was analyzed for 7711 gene expressions by DNA microarray. Some gene expressions showed over 10-fold changes. In particular, the regenerated gene (Reg)2/pancreatitis-associated protein (PAP)l messenger RNA (mRNA) level most markedly increased in the genes, which were clearly expressed in cardiomyocytes rather than in noncardiomyocytes, and it was approximately 2000-fold greater in cardiomyocyles under active myocarditis than normal by real-time reverse transcription polymerase chain reaction analysis. Moreover, we demonstrated that Reg2/PAP1 proteins determined by Western blot analysis and immunohistochemistry and other Reg/PAP family gene expressions were remarkably increased in EAM hearts; in addition, interleukin (IL)-6 expression was significantly related to Reg2/PAP1. It seemed that these data were useful as a reference database of gone-expression changes in cardiomyocytes with myocarditis. The Reg/PAP family, which was found to show dramatically increasing gene expressions by DNA microarray analysis, was suspected to play an important role in myocarditis.

Hereby we report our observations derived from a pilot-study of 39 subjects ( 30 patients with coronary artery disease [ CAD] and 9 non-CAD controls). In this work, we aimed to evaluate MPO-ANCA titer in the human coronary circulation for the first time; and examine its possible association with CAD and some cytokines/inflammatory markers. We found higher mean coronary MPO-ANCA titer in CAD subjects than in non-CAD controls; beside significant positive correlations between MPO-ANCA titers and both C-reactive protein and interleukin-6 levels. Thus, we might suggest the possible involvement of MPO-ANCA in coronary atherogenesis indirectly through modulating some pro-inflammatory cytokines/markers; that a large-scale study of MPO-ANCA in CAD patients may be warranted in the future. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

Background/Purpose. When a pancreatoduodenectomy is to be conducted, preoperative understanding of the vascular anatomy of the pancreatic head is important in order to reduce intraoperative bleeding. Using multislice computed tomography (MS-CT), we investigated the depiction rate and branching of the inferior pancreaticoduodenal artery (IPDA) and dorsal pancreatic artery (DPA), afferent arteries to the pancreatic head. Methods. In 109 patients (68 with pancreatic cancer, 21 with biliary tract cancer, 15 with intraductal papillary mucinous tumor of the pancreas, and 5 others), images were taken, using 64-row MS-CT, in the early and late arterial phases. Results. The depiction rates were 98.2% for the IPDA and 96.3% for the DPA. Branching of the IPDA was categorized into three types: a type in which the IPDA formed a common vessel with the first jejunal branch (72.0%), a type in which the IPDA branched directly from the superior mesenteric artery (18.7%), and a type in which the anterior inferior pancreaticoduodenal artery (AIPDA) and posterior inferior pancreaticoduodenal artery (PIPDA) branched separately (9.3%). DPA branching was categorized into five types, in which the DPA branched from the splenic artery (40.0%), from the common hepatic artery (25.7%), from the superior mesenteric artery (20.0%), and from the celiac artery (8.6%), and a type in which the DPA branching did not follow any of the above patterns (5.7%). Conclusions. MS-CT images of vascular architecture enable evaluation from any angle, which is not possible with conventional angiography, making MS-CT a useful diagnostic imaging technique for understanding the vascular anatomy of the pancreatic head prior to conducting pancreatoduodenectomy for diseases of the pancreatic head region.

We report two cases of pneumatosis intestinalis and hepatic portal venous gas. The first case was in a 67-year-old woman who complained of strong right lower abdominal pain and high fever on the twelfth day after pancreatoduodenectomy (PD) with portal vein (PV) resection. Abdominal X-ray and computed tomography showed hepatic portal venous gas and pneumatosis intestinalis. The emergency laparotomy performed disclosed extensive necrosis of the bowel from the jejunum to the ascending colon. All necrotic parts of the bowel were resected and a jejunostomy was performed. The residual intact small intestine was 30 cm in length. Her postoperative course was stable. This is a rare complication after PD and cannot be cured by any other treatment but surgery. The second case was in a 45-year-old woman with the chief complaint of abdominal pain and constipation. She had a past history of chronic toluene inhalation. Abdominal X-ray and computed tomography also showed hepatic portal venous gas and pneumatosis intestinalis, as well as free air, but no physical examination or laboratory test results supported a diagnosis of bowel necrosis. Hyperbaric oxygen (HBO) therapy effectively controlled the symptoms and signs.

The shortage of organ donors has impeded the development of human hepatocyte transplantation. Immortalized hepatocytes could provide an unlimited supply of transplantable cells. To determine whether immortalized hepatocytes could provide global metabolic support in end-stage liver disease, rat hepatocyte clones were developed by transduction with the gene encoding the Simian virus 40 T antigen (SVT) using the human artificial minichromosome (HAC). The SVLT sequence was excised by FRT recombination. Following HAC infusion, the transduced hepatocytes express SVT, blasticidine resistance (BS), and the PGK promoter TK gene. Forty-six cell clones were obtained and at least partially characterized, as previously described, for albumin, alpha-1-antitrypsin, glucose-6-phosphatase (G6Pase), dipeptidylpeptidase 4 (Dpp4), gamma-glutamyltransferase 1 (Ggt), SVT, and beta-actin expression using RT-PCR. Clones were also assessed for albumin secretion into the culture medium using ELISA. All of the cell line secreted approximately 10 mg/ dl of albumin, which is equivalent to the amount secreted by primary hepatocytes. In further experiments, this cell line will be used for transplantable cells or artificial organ using HAC. These results represent an important step toward the development of immortalized hepatocytes.

Background/Purpose. Pancreatoduodenectomy (PD) is one of the most difficult operations in gastrointestinal surgery. Standard PD ligates and cuts superior mesenteric vein (SMV) branches after the removal of the pancreas head, which leads to congestion and bleeding of these veins. Methods. In this study, we modified the standard PD and first ligated the efferent vessels ( arteries); namely, the gastroduodenal artery and inferior pancreatoduodenal artery (IPDA), before ligating and cutting the corresponding afferent vessels ( veins) of the pancreas head. By doing this, congestion of these veins was relieved and bleeding from the resected surface was substantially prevented. Thirty-six patients ( 18 underwent standard PD and 18 had modified PD) formed the study population. Results. The amount of bleeding in the modified PD group was significantly lower than that in the standard PD group. ( 678 +/- 329 g vs 1225 +/- 375 g, respectively; P < 0.05) However, no difference in operation time was found between the two groups. Conclusions. We believe this modified PD procedure is valuable to enable the safe performance of PD.

This study aimed to clarify detailed and serial electrocardiographic findings in patients with Takotsubo cardiomyopathy from onset to recovery. Nine consecutive women aged 65 to 84 years (mean 74) with Takotsubo cardiomyopathy were investigated. Standard 12-lead electrocardiograms were recorded during hospitalization and ST-segment elevation and T-wave inversion were manually measured daily in each patient. All 9 patients had 4 phases found electrocardiographically. Phase 1 was characterized by ST-segment elevation immediately after onset. Subsequently, T-wave inversion was observed from days 1 to 3 (phase 2), then inverted T waves improved transiently from days 2 to 6 (phase 3). After this phase, giant inverted T waves with QT prolongation appeared and persisted 2 months until recovery (phase 4). Serum creatine kinase levels were increased only at onset. Left ventricular wall motion abnormalities evaluated using echocardiography improved gradually after phase 3 in all patients. Second T-wave inversions (phase 4) were significantly deeper than those of the first one (phase 2; p <0.05). In conclusion, 4 electrocardiographic phases in patients with Takotsubo cardiomyopathy were shown. This observation may be helpful to understand the pathophysiologic process of Takotsubo cardiomyopathy. (C) 2007 Elsevier Inc. All rights reserved.

The role of endostatin in coronary heart disease (CHD) is not well known. This study aimed to investigate the dynamics of endostatin, an antiangiogenic growth factor, within the coronary circulation and to elucidate its relation to coronary collateral formation in patients with CHD. We recruited 72 subjects with suspected or previously diagnosed CHD. Blood samples from the left ventricular (LV) cavity and coronary sinus (CS) were obtained during coronary angiography, and the serum concentration of endostatin was measured by enzyme-linked immunosorbent assay kits. Patients were then divided into 2 groups: the normal group (n = 15) defined as patients with atypical chest pain and no evidence of organic cardiac diseases and the CHD group (n = 57) defined as patients with >= 75% coronary stenosis at coronary angiography and chest pain on exertion. Endostatin in CS sera was significantly elevated in patients with CHD compared with normal subjects (median 79.7 [interquartile range 46.2 to 130.3] vs median 49.6 [interquartile range 29.1 to 84.5] ng/ml, p = 0.02). Spillover of endostatin (CS - LV value) from the coronary circulation in patients with CHD with severe stenosis was higher than in those with moderate stenosis (28.2 [4.8 to 48.61 vs 7.3 [-37.0 to 25.6] ng/ml, p = 0.01). In addition, endostatin production within the coronary circulation was higher in patients with poorly developed collaterals than in those with well-developed collaterals. In conclusion, endostatin is suggested to be produced from the coronary circulation in patients with CHD and may play an important role in the regulation of the growth of coronary collateral vessels. (c) 2007 Elsevier Inc. All rights reserved.

Objective Cardiovascular complication is one of the serious complications in stem cell transplantation (SCT). We measured plasma brain natriuretic peptide (BNP) concentrations in patients who received SCT to evaluate possible cardiac toxicity of the regimens employed in SCT. Patients Ten patients with allogeneic SCT and 5 patients with autologous SCT using myeloablative conditioning regimens were enrolled. The preparative chemotherapy for 8 patients with allogeneic SCT included cyclophosphamide (60 mg/kg i.v. for 2 days) and other drugs and that for autologous SCT included cyclophosphamide (50 mg/kg for 2 days) and other drugs. Total body irradiation (TBI) was employed only in the patients who received allogeneic SCT. Method Plasma BNP was measured using a radioimmunoassay for human BNP before and after SCT. Results In 13 of 15 patients, BNP levels were elevated after SCT. In patients who received a total body irradiation (TBI) of 13.2 Gy, BNP levels were higher than those without irradiation (p=0.01). The BNP level reached a peak within 6 months after SCT in most patients and fell thereafter. But 7 of the 15 patients (46.7%) had an abnormally high level of plasma BNP even after 6 months of SCT which suggests subclinical myocardial damage. Conclusion A rise in plasma BNP was frequently observed after SCT, and may be considered to represent cardiac damage caused by the preparative chemotherapy and/or total body irradiation. Since a rise was noted 6 months after SCT, long-term evaluation of cardiac function is important.

It has already been established that hepatocyte transplantation (HTx) in animal models, such as both chemically and surgically induced acute liver failure, liver-based metabolic disease, and cirrhosis, resulted in significant improvement of liver function and survival. However, the efficacy of hepatocyte transplantation in secondary cholestatic liver disease is not well known. In this study, we transplanted hepatocytes into the spleen of Nagase analbuminemic rats (NARs) with common bile duct ligation (CBDL) to evaluate the function of transplanted hepatocytes by both of serum albumin levels and total bilirubin levels. CBDL was carried out on NARs to induce liver failure. Lewis rat hepatocytes were transplanted in NARs 7 days after CBDL. Animals, in groups of four, underwent the following interventions: group 1-intrasplenic transplantation of 30 x 106 primary Lewis rat hepatocytes in NARs with CBDL (n = 4), group 2-intrasplenic injection of 0.5 ml DMEM in NARs with CBDL (n = 4); group 3-CBDL only (n = 4); group 4-intrasplenic transplantation of 30 x 101 primary Lewis rat hepatocytes in NARs (n = 4). Both bilirubin levels and albumin levels in NARs with CBDL were significantly improved post-HTx. Animals receiving hepatocyte transplantation survived longer than animals in nontransplant control groups. This study indicates that hepatocytes can be transplanted to temporarily provide life-supporting liver-specific metabolic function and prolong the survival in recipient rats with liver failure induced by CBDL.

Many clinical studies have evaluated the inflammatory response (mainly interleukin [IL]-6 and C-reactive protein [CRP]) after percutaneous coronary intervention (PCI) in patients with coronary artery disease (CAD). The aim of this study was to verify the source of possible elevation of IL-6 and CRP after PCI using coronary sinus sampling. We studied 87 subjects who underwent coronary angiography for diagnostic, therapeutic, or follow-up purposes. Blood samples were taken by the PCI team during the catheterization study from the coronary sinus. We measured coronary IL-6 levels by sandwich enzyme-linked immunosorbent assay, and high-sensitivity CRP levels were measured by latex immunonephelometry. The subjects were then classified according to their coronary angiographic findings into non-CAD (no evidence of significant organic CAD), mild CAD (I vessel narrowed), and severe CAD ( 2 vessels narrowed) groups. PCI (including stent deployment) was performed in 16 patients with CAD. The mean coronary IL-6 value was higher in the severe than in the mild CAD group (3.67 +/- 2.48 vs 2.3 +/- 1.15 pg/ml, p = 0.027). The mean coronary IL-6 value was higher in the subjects who underwent PCI than in those who did not (2.9 +/- 1.23 vs 1.87 +/- 0.9 pg/ml, p = 0.037), and the same was found regarding CRP (1.244 +/- 0.72 vs 0.498 +/- 0.51 mg/L, p = 0.032). The coronary IL-6 values correlated positively with the coronary CRP values (r = 0.374, p = 0.017). In conclusion, the increase in coronary IL-6 and CRP levels after PCI in patients with CAD might be attributed to their release from the coronary atheroma secondary to the direct mechanical effect applied on the atheroma itself by balloon inflation and stent deployment. (c) 2006 Elsevier Inc. All rights reserved.

Erythropoietin (EPO) has been known to have cytoprotective effects on several types of tissues, presumably through modulation of apoptosis and inflammation. The effect of EPO on myocardial inflammation, however, has not yet been clarified. We investigated the cardioprective effects of EPO in rats with experimental autoimmune myocarditis (EAM). Seven-week-old Lewis rats immunized with cardiac myosin were treated either with EPO or vehicle and were examined on day 22. EPO attenuated the functional and histological severity of EAM along with suppression of mRNAs of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in the hearts as well as a reduction of apoptotic cardiomyocytes. The EPO receptor (EPO-R) was upregulated in the myocardium of EAM compared with that of healthy rats. These results may suggest that EPO ameliorated the progression of EAM by modulating myocardial inflammation and apoptosis. (c) 2006 Elsevier Inc. All rights reserved.

Clinical implication of mechanical alternans is yet unclear. It may suggest the risk for sudden death in patients with chronic heart failure. Two cases with dilated cardiomyopathy showed mechanical alternans during, diagnostic cardiac catheterization. They suddenly died due to ventricular fibrillation before the induction of beta-blocker therapy. Patients with mechanical alternans should be treated under intense monitoring until the induction of beta-blocker therapy.

A 45-year-old female who had cardiac Surgery 40 years earlier was transferred to our hospital because of refractory fever. Echocardiography showed an intrapericardial mass. Gallium-67 (Ga-67) scintigraphy revealed abnormal accumulation at the same site of the intrapericardial mass and thoracoscopy revealed that the mass was a pericardial abscess (PA). After surgical resection, drainage and antibiotic therapy, her fever subsided and the abnormal accumulation of Ga-67 disappeared. This case showed a very rare clinical Course of PA and the importance of Ga-67 scintigraphy for its diagnosis.

Although increased external load initially induces cardiac hypertrophy with preserved contractility, sustained overload eventually leads to heart failure through poorly understood mechanisms. Here we describe a conditional transgenic system in mice characterized by the sequential development of adaptive cardiac hypertrophy with preserved contractility in the acute phase and dilated cardiomyopathy in the chronic phase following the induction of an activated Akt1 gene in the heart. Coronary angiogenesis was enhanced during the acute phase of adaptive cardiac growth but reduced as hearts underwent pathological remodeling. Enhanced angiogenesis in the acute phase was associated with mammalian target of rapamycin-dependent induction of myocardial VEGF and angiopoietin-2 expression. Inhibition of angiogenesis by a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Thus, both heart size and cardiac function are angiogenesis dependent, and disruption of coordinated tissue growth and angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure.

Background - It is unclear how amiodarone therapy exerts its effects on left ventricular remodeling and cardiac sympathetic nerve function in chronic heart failure. We investigated long-term effects of amiodarone on rat dilated cardiomyopathy after healing of cardiac myosin - induced autoimmune myocarditis. Methods and Results - Rats were treated with oral amiodarone or vehicle for 6 weeks. We determined cardiac function, left ventricular remodeling, and cardiac sympathetic nerve function with iodine-125-labeled metaiodobenzylguanidine ([I-125]MIBG). Amiodarone treatment improved left ventricular pressure, central venous pressure, and rate of isovolumetric contraction and decreased ventricular weight (P < 0.005). Expression of cytokine mRNA was unchanged; expression of atrial natriuretic peptide, collagen III, and transforming growth factor-β(1) mRNA was decreased in amiodarone-treated rats (P < 0.05). Phenotype of myosin heavy chain was moved toward that of normal rats by amiodarone. Initial myocardial uptake of MIBG decreased by 67% (P < 0.001) and washout rate accelerated by 221% in rats with chronic heart failure compared with normal rats. Whereas amiodarone decreased the initial uptake by 71% in normal rats, amiodarone decelerated the early washout and the late washout and improved the late myocardial distribution of MIBG in rats with chronic heart failure (257% compared with vehicle-treated rats with chronic heart failure; P < 0.01). In proportion to MIBG distributions, cardiac tissue catecholamines were increased by amiodarone treatment. Conclusions - Long-term amiodarone treatment prevented left ventricular remodeling and improved cardiac function in rat dilated cardiomyopathy. Long-term amiodarone treatment also restored cardiac sympathetic tone to hold norepinephrine in the heart.

The disease course of acute myocarditis has a wide spectrum and the predictors of the prognosis in patients with acute myocarditis have not yet been established. In the pathogenesis of myocarditis, the cytokine environment is important. In this study, we examined the predictive values of serum levels of interleukin-10 (IL-10) and IL-12 in the short-term prognosis of patients with acute myocarditis. Twenty-four consecutive patients who had been diagnosed as having acute active myocarditis were analyzed and monitored for 2 months. The patients with myocarditis were divided into the survival group (n=16) and the non-survival group (n-8). Initial serum levels of IL-10 (P=0.0015) and IL-12 (P=0.012) in the non-survival group were significantly higher than those of the survival group, and there was a significant correlation between IL-10 and IL-12 levels (P<0.0001). The univariate analyses showed that increased serum levels of IL-10 (hazard ratio 1.041, F=0.0004) and IL-12 (hazard ratio 1.128, P-0.0346) were significant predictors of mortality. In the Kaplan-Meier analysis, high levels of IL-10 ( greater than or equal to7.0 pg/ml) (P=0.0239) strongly predicted high mortality. In conclusion, the elevation in serum IL-10 levels at the initial phase appeared to predict poor short-term prognosis in patients with acute myocarditis. (C) 2004 European Society of Cardiology. Published by Elsevier B.V All rights reserved.

Patients with diabetes and other obesity-linked conditions have increased susceptibility to cardiovascular disorders(1). The adipocytokine adiponectin is decreased in patients with obesity-linked diseases(2). Here, we found that pressure overload in adiponectin-deficient mice resulted in enhanced concentric cardiac hypertrophy and increased mortality that was associated with increased extracellular signal-regulated kinase (ERK) and diminished AMP-activated protein kinase (AMPK) signaling in the myocardium. Adenovirus-mediated supplemention of adiponectin attenuated cardiac hypertrophy in response to pressure overload in adiponectin-deficient, wild-type and diabetic db/db mice. In cultures of cardiac myocytes, adiponectin activated AMPK and inhibited agonist-stimulated hypertrophy and ERK activation. Transduction with a dominant-negative form of AMPK reversed these effects, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium through activation of AMPK signaling. Adiponectin may have utility for the treatment of hypertrophic cardiomyopathy associated with diabetes and other obesity-related diseases.

Background-3-Hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) inhibit myocyte hypertrophy in vitro and ameliorate the progression of cardiac remodeling in vivo, possibly because of inhibition of the small GTPase Rac1. The role of Rac1 in mediating myocyte apoptosis is not known. beta-Adrenergic receptor (betaAR)-stimulated myocyte apoptosis is mediated via activation of c-Jun NH2-terminal kinase (JNK), leading to activation of the mitochondrial death pathway. We hypothesized that betaAR-stimulated apoptosis in adult rat ventricular myocyte (ARVMs) is mediated by Rac1 and inhibited by statins. Methods and Results-betaAR stimulation increased apoptosis, as assessed by transferase-mediated nick-end labeling, from 5 +/- 1% to 24 +/- 2%. betaAR stimulation also increased Rac1 activity. Adenoviral overexpression of a dominant-negative mutant of Rac1 inhibited betaAR-stimulated apoptosis, JNK activation, cytochrome C release, and caspase-3 activation. Cerivastatin likewise inhibited the betaAR-stimulated activation of Rac1, decreased betaAR-stimulated apoptosis to 11 +/- 2%, and inhibited JNK activation, cytochrome C release, and caspase-3 activation. Conclusions-betaAR stimulation causes Rac1 activation, which is required for myocyte apoptosis and leads to activation of JNK and the mitochondrial death pathway. Cerivastatin inhibits betaAR-stimulated activation of Rac1 and thereby inhibits JNK-dependent activation of the mitochondrial death pathway and apoptosis. The beneficial effects of statins on the myocardium may be mediated in part via inhibition of Rac1-dependent myocyte apoptosis.