Manabu Shiraishi

Alternatively activated macrophages determine repair of the infarcted adult murine heart

Alternatively activated (also known as M2) macrophages are involved in the repair of various types of organs. However, the contribution of M2 macrophages to cardiac repair after myocardial infarction (MI) remains to be fully characterized. Here, we identified CD206+F4/80+CD11b+ M2-like macrophages in the murine heart and demonstrated that this cell population predominantly increases in the infarct area and exhibits strengthened reparative abilities after MI. We evaluated mice lacking the kinase TRIB1 (Trib1-/-), which exhibit a selective depletion of M2 macrophages after MI. Compared with control animals, Trib1-/- mice had a catastrophic prognosis, with frequent cardiac rupture, as the result of markedly reduced collagen fibril formation in the infarct area due to impaired fibroblast activation. The decreased tissue repair observed in Trib1-/- mice was entirely rescued by an external supply of M2-like macrophages. Furthermore, IL-1α and osteopontin were suggested to be mediators of M2-like macrophage-induced fibroblast activation. In addition, IL-4 administration achieved a targeted increase in the number of M2-like macrophages and enhanced the post-MI prognosis of WT mice, corresponding with amplified fibroblast activation and formation of more supportive fibrous tissues in the infarcts. Together, these data demonstrate that M2-like macrophages critically determine the repair of infarcted adult murine heart by regulating fibroblast activation and suggest that IL-4 is a potential biological drug for treating MI.

Epicardial Placement of Mesenchymal Stromal Cell-sheets for the Treatment of Ischemic Cardiomyopathy; In Vivo Proof-of-concept Study

Transplantation of bone marrow mesenchymal stromal cells (MSCs) is an emerging treatment for heart failure. We have reported that epicardial placement of MSC-sheets generated using temperature-responsive dishes markedly increases donor MSC survival and augments therapeutic effects in an acute myocardial infarction (MI) model, compared to intramyocardial (IM) injection. This study aims to expand this knowledge for the treatment of ischemic cardiomyopathy, which is likely to be more difficult to treat due to mature fibrosis and chronically stressed myocardium. Four weeks after MI, rats underwent either epicardial MSC-sheet placement, IM MSC injection, or sham treatment. At day 28 after treatment, the cell-sheet group showed augmented cardiac function improvement, which was associated with over 11-fold increased donor cell survival at both days 3 and 28 compared to IM injection. Moreover, the cell-sheet group showed improved myocardial repair, in conjunction with amplified upregulation of a group of reparative factors. Furthermore, by comparing with our own previous data, this study highlighted similar dynamics and behavior of epicardially placed MSCs in acute and chronic stages after MI, while the acute-phase myocardium may be more responsive to the stimuli from donor MSCs. These proof-of-concept data encourage further development of the MSC-sheet therapy for ischemic cardiomyopathy toward clinical application.

Allogeneic Mesenchymal Stromal Cells Transplanted Onto the Heart Surface Achieve Therapeutic Myocardial Repair Despite Immunologic Responses in Rats.

Background Transplantation of allogeneic mesenchymal stromal cells (MSCs) is a promising treatment for heart failure. We have shown that epicardial placement of cell sheets markedly increases donor cell survival and augments therapeutic effects compared with the current methods. Although immune rejection of intramyocardially injected allogeneic MSCs have been suggested, allogeneic MSCs transplanted on the heart surface (virtual space) may undergo different courses. This study aimed to elucidate immunologic response against epicardially placed allogeneic MSCs, rejection or acceptance of these cells, and their therapeutic effects for heart failure. Methods and Results At 4 weeks after coronary artery ligation, Lewis rats underwent epicardial placement of MSC sheets from syngeneic Lewis or allogeneic Fischer 344 rats or sham treatment. At days 3 and 10 after treatment, similar ratios (≈50% and 30%, respectively) of grafted MSCs survived on the heart surface in both MSC sheet groups. By day 28, survival of syngeneic MSCs was substantially reduced (8.9%); survival of allogeneic MSCs was more extensively reduced (0.2%), suggesting allorejection. Correspondingly, allogeneic MSCs were found to have evoked an immunologic response, albeit low level, as characterized by accumulation of CD4+ T cells and upregulation of interleukin 6. Despite this alloimmune response, the allogeneic MSC sheet achieved myocardial upregulation of reparative factors, enhanced repair of the failing myocardium, and improved cardiac function to the equivalent degree observed for the syngeneic MSC sheet. Conclusions Allogeneic MSCs placed on the heart surface evoked an immunologic response; however, this allowed sufficient early phase donor cell survival to induce equivalent therapeutic benefits to syngeneic MSCs. Further development of this approach toward clinical application is warranted.

GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

Summary A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.

Hepatic Artery Pseudoaneurysm with Extrahepatic Biliary Obstruction

Hepaticartery pseudoaneurysms are a rare complication of chronic pancreatitis. However, giant pseudoaneurysms (80 mm) and complicated biliary obstructions are extremely rare. This article reports a 75 year-old man with chronic pancreatitis that presented as upper abdominal pain and obstructive jaundice. Computed tomography revealed a hepatic artery pseudoaneurysm measuring 80 × 72 × 70 mm. We performed aneurysm resection and common hepatic artery bypass, using a great saphenous vein graft in the patient. The postoperative course was uneventful, and he was discharged on the 10th postoperative day. However, on the 135th postoperative day, he died of massive hemorrhage into the peritoneal cavity.

Mycotic superior mesenteric pseudoaneurysm draining into a vein

A 46-year-old man with a medical history notable only for schizophrenia was admitted to hospital with complaints of general fatigue and high fever. Transthoracic echocardiography on day 6 after admission demonstrated a large vegetation (17 mm) on the anterior leaflet of the mitral valve with mild regurgitation and mild aortic regurgitation. The patient also complained of abdominal pain. Abdominal computed tomography showed a remarkable enlargement of the superior mesenteric artery aneurysm (SMAA). An excision of the SMAA and double valve replacement was performed, and the patient was administered a six-week course of intravenous antibiotic therapy.

IL-4 as a Repurposed Biological Drug for Myocardial Infarction through Augmentation of Reparative Cardiac Macrophages: Proof-of-Concept Data in Mice

Recent research has shown that reparative (alternatively activated or M2) macrophages play a role in repair of damaged tissues, including the infarcted hearts. Administration of IL-4 is known to augment M2 macrophages. This translational study thus aimed to investigate whether IL-4 administration is useful for the treatment of myocardial infarction. Long-acting IL-4 complex (IL-4c; recombinant IL-4 mixed with anti-IL-4 monoclonal antibody as a stabilizer) was administered after coronary artery ligation in mice. It was observed that IL-4c administration increased accumulation of CD206+F4/80+ M2-like macrophages predominantly in the injured myocardium, compared to the control. Sorted cardiac M2-like macrophages highly expressed wide-ranging tissue repair-related genes. Indeed, IL-4c administration enhanced cardiac function in association with reduced infarct size and enhanced tissue repair (strengthened connective tissue formation, improved microvascular formation and attenuated cardiomyocyte hypertrophy). Experiments using Trib1−/− mice that had a depleted ability to develop M2 macrophages and other in-vitro studies supported that these IL-4-mediated effects were induced via M2-like macrophages. On the other hand, when administered at Day 28 post-MI, the effects of IL-4c were diminished, suggesting a time-frame for IL-4 treatment to be effective. These data represent proof-of-concept of efficacy of IL-4 treatment for acute myocardial infarction, encouraging its further development.

Surgical treatment for thoracic aneurysms: comparison of stent grafting and open surgery.

OBJECTIVES Early and mid-term results of stent graft (SG) treatment for thoracic aortic aneurysms (thoracic endovascular aneurysm repair: TEVAR) were retrospectively compared with open surgical treatment. METHODS The records of 213 patients in whom single thoracic aortic aneurysm repairs had been performed in our department from January 2006 through August 31, 2009 were reviewed. Acute aortic dissection was excluded. Each case was reviewed for indications for TEVAR from an anatomical standpoint. Among 62 cases in which TEVAR was indicated, 30 (SG group) were treated by TEVAR and 32, by open surgery (OP group). Early and mid-term results were analyzed retrospectively in both groups. RESULTS There were no operative deaths in either group. The SG group demonstrated significantly less operative bleeding, a shorter operative time, and shorter postoperative hospital stay compared with the OP group. There were 3 deaths in the SG group and 4 in the OP group, which occurred within an average of 656.4 days during the follow up period. The 3 year actuarial survival rate was 88.7% in the SG group and 87.1% in the OP group, and there were no significant differences between the groups. CONCLUSION Although early and mid-term results of TEVAR and open surgery were similar, TEVAR is generally less invasive and may be preferable for high-risk patients, compared with open surgical repair. (English Translation of Jpn J Vasc Surg 2010; 19: 51-56.).

Cardiac varix in the right atrium.

A 73-year old man underwent transthoracic and transoesophageal echocardiography and computed tomography, which revealed what appeared to be an asymptomatic primary mobile tumour located in the right atrium. During surgery, the mass was found to be associated with the right atrial septum and was subsequently resected. Histopathology of the mass revealed a cardiac varix with phleboliths. The patient had an uneventful postoperative course and no signs of recurrence at the 10-month follow-up.

Late disruption of axillo-bifemoral bypass graft

Figure 1 (A) A 70 mm × 50mm × 60mm pulsatile, erythematous, indolent mass was detected in the left subclavicular region. (B) Computed tomography revealed a rupture of the left axillo-bifemoral bypass graft with the formation of a false aneurysm