Hisashi Sakaguchi

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 CaCl2-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. Conclusion—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.

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.

Modified gastric pull-up reconstructions following pharyngolaryngectomy with total esophagectomy

Reconstruction following pharyngolaryngectomy with total esophagectomy is a challenging surgery to perform. Between April 2008 and August 2012, three types of modified gastric pull-up reconstruction procedures, including a gastric tube creation combined with a free jejunal transfer (n = 7), elongated gastric tube creation with vascular anastomoses (n = 2) and pedunculated gastric tube creation with Roux-en-Y anastomosis (n = 5), were performed after pharyngolaryngectomy with total esophagectomy. To clarify feasibility of these reconstructive methods, we retrospectively analyzed the short-term outcomes. There were no graft failures. Salivary fistulae were observed in two cases after high pharyngoenteral anastomoses due to oropharyngeal extension of hypopharyngeal cancers. Overall morbidity rate was 21.4%, and no deaths occurred. Although the operation time was shortest for pedunculated gastric tube reconstructions, morbidity rates were similar among all methods. All three types of modified gastric pull-up reconstruction procedures can be performed safely. We can choose one of these methods according to the tumor status and the patient condition, understanding advantages and disadvantages of each procedure.

ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism

A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure.

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-yearold 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.

Superficial spreading type extrahepatic bile duct cancer with lymphatic micrometastasis: Report of a case

We report herein the case of a 69-year-old woman with extrahepatic bile duct cancer which had developed superficially along the ductal mucosa without penetrating the fibromuscularis. She underwent a pancreatoduodenectomy; however, micrometastases were found histologically in the regional lymph nodes and she died with involved para-aortic lymph nodes and bone metastases 14 months after the operation.

A simple method of intraoperative preparation of a stent graft for distal aortic arch aneurysm

J Thorac Cardiovasc Surg Takaji, Yukihiro Katayama and Michio Kawasuji Ryuji Kunitomo, Shigeyuki Tsurusaki, Hisashi Sakaguchi, Ichiro Ideta, Kentaro arch aneurysm A simple method of intraoperative preparation of a stent graft for distal aortic http://jtcs.ctsnetjournals.org/cgi/content/full/125/6/1535 located on the World Wide Web at: The online version of this article, along with updated information and services, is

A resuscitated case of cardiopulmonary arrest due to massive hemoptysis caused by a ruptured thoracic aortic aneurysm

Dear Editor, We report a resuscitated case of cardiopulmonary arrest (CPA) following massive hemoptysis due to a ruptured thoracic aortic aneurysm (TAA). A 73-year-old man was admitted with a sudden onset of hemoptysis. He presented with atrial fibrillation, and he had been taking warfarin (1 mg/day). He had not been previously diagnosed as having a TAA and had had no episode of hemoptysis. On admission, he was lucid with the following vital data: blood pressure, 143/107 mmHg; pulse rate, 90–110 b.p.m.; respiratory rate, 20/min. His breathing sound was reduced in his left lung field. Laboratory tests showed: hemoglobin, 14.7 g/dL; total leukocyte count, 10,800/mm; platelet count, 135,000/mm; PT (INR), 1.17; d-dimer, 29.4 μg/mL. A chest X-ray revealed a hazy shadow in the patient’s left lung field (Fig. 1A). A contrast-enhanced chest computed tomography scan showed a leakage of the contrast material from the TAA and consolidated lung tissue adjacent to the TAA (Fig. 1B). He was diagnosed as having a ruptured TAA into the tracheobronchial trees or the lung, and an emergent endovascular stent-grafting was scheduled. Just before the induction of general anesthesia, CPA following sudden massive hemoptysis occurred. He was intubated immediately, and we started cardiopulmonary resuscitation (CPR). An endovascular intervention was also started under the CPR. We inserted the stent-graft through the femoral artery with fluoroscopy guidance. After the dilation of the stent-graft with an endovascular balloon, the patient was resuscitated. The duration of the CPR was 67 min; however, we had to interrupt the chest compression several times during the fluoroscopy guidance. During the CPR, his electrocardiogram revealed pulseless electrical activity and mechanical ventilation was continued with 100% oxygen; however, the lowest PaO2 was 52 mmHg and the highest PaCO2 was 98 mmHg. The lowest value of

Successful Therapy of Brachiocephalic Arteriogastric Fistula After Esophagectomy

We report the case of an 86-year-old man, who had undergone subtotal esophagectomy and reconstruction with a gastric tube through the retrosternal route 7 years ago, who was referred for treatment of a brachiocephalic arteriogastric fistula. An emergency stent-graft placement was performed to prevent massive bleeding from the fistula. After 2 weeks, a follow-up esophagogastroscopy revealed that the gastric tube ulcer had been penetrated, and the stent graft was exposed. Therefore, surgical treatment was indicated. After a carotid-carotid arterial bypass graft was made, the brachiocephalic artery was resected with the stent graft and the gastric wall. The defect between the cervical esophagus and the remnant gastric tube was replaced by a free jejunal graft. The patient tolerated these procedures well and was transferred to the referral hospital 3 months after surgery. Therefore, both an early diagnosis and the administration of multidisciplinary treatment are essential to save patients presenting with an arterioenteric fistula.

Efficacy and Safety of Tolvaptan in Infants after Open Heart Surgery

Background: Reports on the efficacy of tolvaptan, which is a selective vasopressin V2 antagonist, in infants who undergo cardiac surgery are rare. We evaluated the efficacy and safety of tolvaptan to manage early fluid retention in infants following open heart surgery. Methods: Pediatric patients under the age of 1 year who underwent biventricular repair with CPB were received conventional diuretics. Additionally, tolvaptan was administered in 18 patients two days after the administration of conventional diuretics when conventional diuretics did not effectively control fluid. For the evaluation of the effect of tolvaptan, the cumulative 24-h urine volume was measured. Changes in laboratory values, cardio hemodynamic factors, and all adverse events were also evaluated. Results: The cumulative 24-h urine volume after 1st tolvaptan administration increased significantly compared with the urine volume before the administration (Day 3 vs. Day 4, 56.0 ± 15.0 vs. 84.2 ± 20.6 mL/kg; p=0.0002). Similarly, the cumulative 24-h urine volume after 2nd tovaptan administration were significantly larger than that before the tolvaptan administration (Day 5 vs. Day 3, 85.9 ± 32.2 vs 56.0 ± 15.0 mL/kg; p=0.003). There were no significant differences in hemodynamical factors and laboratory values on the tolvaptan administration. We also found that no adverse events were present. Conclusions: The addition of tolvaptan to conventional diuretics increases urine volume without major adverse events, and could be beneficial to control fluid in infants who underwent open heart surgery.