Hidetoshi Akashi

Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial

BACKGROUND Preclinical studies have established that implantation of bone marrow-mononuclear cells, including endothelial progenitor cells, into ischaemic limbs increases collateral vessel formation. We investigated efficacy and safety of autologous implantation of bone marrow-mononuclear cells in patients with ischaemic limbs because of peripheral arterial disease. METHODS We first did a pilot study, in which 25 patients (group A) with unilateral ischaemia of the leg were injected with bone marrow-mononuclear cells into the gastrocnemius of the ischaemic limb and with saline into the less ischaemic limb. We then recruited 22 patients (group B) with bilateral leg ischaemia, who were randomly injected with bone marrow-mononuclear cells in one leg and peripheral blood-mononuclear cells in the other as a control. Primary outcomes were safety and feasibility of treatment, based on ankle-brachial index (ABI) and rest pain, and analysis was per protocol. FINDINGS Two patients were excluded from group B after randomisation. At 4 weeks in group B patients, ABI was significantly improved in legs injected with bone marrow-mononuclear cells compared with those injected with peripheral blood-mononuclear cells (difference 0.09 [95% CI 0.06-0.11]; p<0.0001). Similar improvements were seen for transcutaneous oxygen pressure (13 [9-17]; p<0.0001), rest pain (-0.85 [-1.6 to -0.12]; p=0.025), and pain-free walking time (1.2 [0.7-1.7]; p=0.0001). These improvements were sustained at 24 weeks. Similar improvements were seen in group A patients. Two patients in group A died after myocardial infarction unrelated to treatment. INTERPRETATION Autologous implantation of bone marrow-mononuclear cells could be safe and effective for achievement of therapeutic angiogenesis, because of the natural ability of marrow cells to supply endothelial progenitor cells and to secrete various angiogenic factors or cytokines.

Obstruction of st jude medical valves in the aortic position: histology and immunohistochemistry of pannus

OBJECTIVE This study aims to reveal the morphological, histological, and immunohistochemical mechanism of pannus formation using resected pannus tissue from patients with prosthetic valve dysfunction. METHOD Eleven patients with prosthetic valve (St Jude Medical valve) dysfunction in the aortic position who underwent reoperation were studied. We used specimens of resected pannus for histological staining (hematoxylin and eosin, Grocotts, azan, elastica van Gieson) and immunohistochemical staining (transforming growth factor-beta, transforming growth factor-beta receptor 1, alpha-smooth muscle actin, desmin, epithelial membrane antigen, CD34, factor VIII, CD68KP1, matrix metalloproteinase-1, matrix metalloproteinase-3, and matrix metalloproteinase-9). RESULTS Pannus without thrombus was observed at the periannulus of the left ventricular septal side; it extended into the pivot guard, interfering with the movement of the straight edge of the leaflet. The histological staining demonstrated that the specimens were mainly constituted with collagen and elastic fibrous tissue accompanied by endothelial cells, chronic inflammatory cells infiltration, and myofibroblasts. The immunohistochemical findings showed significant expression of transforming growth factor-beta, transforming growth factor-beta receptor 1, CD34, and factor VIII in the endothelial cells of the lumen layer; strong transforming growth factor-beta receptor 1, alpha-smooth muscle actin, desmin, and epithelial membrane antigen in the myofibroblasts of the media layer; and transforming growth factor-beta, transforming growth factor-beta receptor 1, and CD68KP1 in macrophages of the stump lesion. CONCLUSIONS Pannus appeared to originate in the neointima in the periannulus of the left ventricular septum. The structure of the pannus consisted of myofibroblasts and an extracellular matrix such as collagen fiber. The pannus formation after prosthetic valve replacement may be associated with a process of periannular tissue healing via the expression of transforming growth factor-beta.

Aortic root replacement with a composite graft: Results of 69 operations in 66 patients

Between December 1973 and December 1992, 66 patients underwent aortic root replacement at our hospital. The mean age of the patients was 42.5 years (range, 20 to 71 years); 44 patients were male and 22 were female. Of the 66 patients, 34 (51.5%) had clinical stigmata of Marfans syndrome. The aortic pathology requiring aortic root replacement was annuloaortic ectasia in 59 patients, aortic dissection in 5, and progressive dilatation of the ascending aorta after aortic valve replacement in 2. Twelve of the 59 patients with annuloaortic ectasia also had aortic dissection. The operative techniques used were the Bentall technique in 36 operations, the Cabrol technique in 21, the aortic button technique in 3, and other miscellaneous techniques in 9. The hospital mortality rate for the primary operation was 10.6% (7 patients), and the late mortality rate was 20.3% (12 patients). Four of the late deaths were related to the graft valve prosthesis, and 6 were related to the progression of aneurysmal diseases on the remaining aorta. The survival rate was 71.0% at 10 years. Pseudoaneurysm at the suture lines was detected in 7 patients, 6 of whom had been treated with the Bentall technique, and 5 patients also had Marfans syndrome. No patients having aortic root replacement with the Cabrol technique have required reoperation for pseudoaneurysms.(ABSTRACT TRUNCATED AT 250 WORDS)

Obstruction of St Jude Medical Valves in the Aortic Position: A Consideration for Pathogenic Mechanism of Prosthetic Valve Obstruction:

Between 1995 and 2000, 8 patients with St. Jude Medical (SJM) valves in the aortic position required 9 redo valve replacement for prosthetic valve obstruction. Obstruction of the prosthetic valve was diagnosed by simultaneous echocardiography and cineradiography, and process of restricted leaflet movement that progressed to hemodynamic impairment was observed by serial studies in three recent patients. An oral anticoagulation was considered to be adequate in all patients except one patient who had withdrawal of warfrain. Pannus was the sole cause of valve obstruction in seven events in 6 patients, and both thrombus and pannus in 2 patients. Pannus overgrowth was found on the inflow aspect of the SJM valve, and involved the ends of the straight edge of the leaflets over pivot guards. These results suggest that pannus might play the primary role in development of obstruction of aortic SJM valves in patients on adequate oral anticoagulation.

Aneurysm of aberrant right subdavian artery arising from diverticulum of kommerell. Report of a case with tracheal compression

A 74-year-old woman presented with severe dyspnea without dysphagia. Computed tomographic scans and Digital subtraction angiography revealed the left aortic arch with an aberrant right subclavian artery arising from the Kommerells diverticulum and tracheal compression. The aortic arch and the Kommerells diverticulum were aneurysmal and were responsible for this compression. Surgical relief was accomplished by replacement of the aortic arch and reconstruction of the four brachiocephalic vessels with vascular prostheses through a median sternotomy incision extending into the right supraclavicular region.

Obstruction of St. Jude Medical Valves in the Aortic Position: Plasma Transforming Growth Factor Type Beta 1 in Patients With Pannus Overgrowth

The study investigated the hypothesis that plasma transforming growth factor type beta 1 (TGF-beta1) initiated pannus overgrowth in cases with aortic prosthetic valve dysfunction (PVD). Patients with obstruction of an aortic St. Jude Medical valve in 26 cases (PVD group) and without obstruction in 48 cases (control group) were studied. Plasma TGF-beta1, the intensity of the prothrombin time-international normalized ratio (PT-INR), and the interruption of an oral anticoagulant medicine were conducted. Plasma TGF-beta1 levels in the PVD group (87.7 +/- 29.2 ng/mL) were significantly higher (P < 0.05) than in the control group (73.7 +/- 25.2 ng/mL). The interruption of an oral anticoagulant medicine in 54% of the PVD group versus 12% of the control group was identified (P < 0.001). The mean value of the PT-INR in the PVD group (1.75 +/- 0.30) and control group (1.75 +/- 0.30) was not significantly different (P = 0.82). In conclusion, elevated levels of plasma TGF-beta1 may play a role in pannus overgrowth.

Partial brachiocephalic perfusion in aortic arch replacement

Eleven patients who underwent replacement of the aortic arch or adjacent areas for aneurysmal disease between 1989 and 1991, using hypothermic cardiopulmonary bypass at 20° to 23°C with partial brachiocephalic perfusion, were studied. Selective perfusion of the innominate artery was performed in all 11 patients through the right axillary artery, while partial brachiocephalic perfusion was carried out using a separate arterial roller pump with a perfusion flow rate of 10ml/kg per min. Direct cannulation to the left common carotid and left subclavian artery was not performed in this method. There were 4 men and 7 women who ranged in age from 26 to 78 years, with a mean age of 56 years. The etiology of aneurysmal disease was aortic dissection in 10 patients, and aortitis syndrome in 1. The cardiopulmonary bypass time was 214.3±39.3 min, aortic cross-clamp time 131.5±33.4 min, and partial brachiocephalic perfusion time 57.6±15.1 min. There were three operative deaths (27.3%), the causes being multiple organ failure, acute peritonitis, and infection of the composite graft in the ascending aorta, in one patient each, respectively. However, there were no deaths related to the technique of partial brachiocephalic perfusion and no neurological complications were seen in this series. Thus, we believe that partial brachiocephalic perfusion under hypothermic cardiopulmonary bypass is safe and effective in surgery for aortic aneurysms involving the aortic arch.Twenty patients with aneurysm or dissection of the aortic arch underwent surgical treatment using partial brachiocephalic perfusion (PBP). The right subclavian artery (SA) and common femoral artery were separately cannulated and perfused by individual pump heads. The flow to SA was 4.5-11 (9.9 +/- 1.4) ml/min/kg. The mean distal stump pressure of the left superficial temporal arteries before beginning the CPB were 36-64 (50.6 +/- 8.3) mmHg. The rectal temperature during PBP was maintained at 20.1-25.0 degrees C. The PBP time ranged 32 to 157 min. We studied the oxygen saturation of left internal jugular vein (SjO2) and cerebral circulatory index (CCI) during the PBP. SjO2 ranged from 72.9 to 99.4% and CCI were maintained at more than twice the CCI measured before beginning the CPB. We applied this simplified method (PBP) to the 20 patients with aortic aneurysms. No neurological complication were seen in these 19 patients without one patient. These clinical studies suggest that the PBP under hypothermic CPB is a safe and reliable method of cerebral protection for replacement of the aortic arch.

The impact of preoperative identification of the Adamkiewicz artery on descending and thoracoabdominal aortic repair

OBJECTIVE To investigate the impact of preoperative identification of the Adamkiewicz artery (AKA) on prevention of spinal cord injury (SCI) through the multicenter Japanese Study of Spinal Cord Protection in Descending and Thoracoabdominal Aortic Repair (JASPAR) registry. METHODS Between January 2000 and October 2011, 2435 descending/thoracoabdominal aortic repairs were performed, including 1998 elective repairs and 437 urgent repairs, in 14 major centers in Japan. The mean patient age was 67 ± 13 years, and 74.2% were males. There were 1471 open repairs (ORs), including 748 descending and 137 thoracoabdominal extent [Ex] I, 136 Ex II, 194 Ex III, 115 Ex IV, and 138 Ex V, and 964 endovascular repairs (EVRs). Of the 2435 patients, 1252 (51%) underwent preoperative magnetic resonance or computed tomography angiography to identify the AKA. RESULTS The AKA was identified in 1096 of the 1252 patients who underwent preoperative imaging (87.6%). Hospital mortality was 9.2% (n = 136) in those who underwent OR and 6.4% (n = 62) in those who underwent EVR. The incidence of SCI was 7.3% in the OR group (descending, 4.2%; Ex I, 9.4%; Ex II, 14.0%; Ex III, 14.4%; Ex IV, 4.2 %; Ex V, 7.2%) and 2.9% in the EVR group. The risk factors for SCI in ORs were advanced age, extended repair, emergency, and occluded bilateral hypogastric arteries. In ORs of the aortic segment involving the AKA, having no AKA reconstruction was a significant risk factor for SCI (odds ratio, 2.79, 95% confidence interval, 1.14-6.79; P = .024). CONCLUSIONS In descending/thoracoabdominal aortic repairs, preoperative AKA identification with its adequate reconstruction or preservation, especially, in ORs of aortic pathologies involving the AKA, would be a useful adjunct for more secure spinal cord protection.

Spontaneous rupture of the ascending aorta

A case of spontaneous non-traumatic rupture of the thoracic aorta in a hypertensive patient is presented. The clinical findings suggested acute aortic dissection, and a large pericardial effusion was detected by echocardiography. The typical angiographic features of aortic dissection were not found. Autopsy revealed a longitudinal intimal tear and a rupture in the postero-lateral aspect of the ascending aorta. No false lumen was seen in the ascending aorta. When acute intrapericardial or intrapleural bleeding develops with no evidence of aortic aneurysm or dissection, spontaneous aortic rupture should be suspected.

Hepatocyte growth factor promotes an anti-inflammatory cytokine profile in human abdominal aortic aneurysm tissue

Abdominal aortic aneurysm (AAA) is characterized by the destruction of tissue architecture due to chronic inflammation of unknown etiology. Recent studies have indicated that control of inflammation is a promising therapeutic strategy; however, no established pharmacological intervention is currently available for AAA. We found that hepatocyte growth factor (HGF) was expressed in aneurysmal tissue, and colocalized with von Willebrand factor, the endothelial cell marker, in the most damaged part of the aneurysmal walls. In ex vivo cultures of human AAA tissue, exogenously added HGF in the presence of tumor necrosis factor-alpha (TNF-α) enhanced the secretion of anti-inflammatory cytokine interleukin-10 (IL-10) and suppressed the secretion of proinflammatory monocyte/macrophage chemotactic protein-1 (MCP-1). The angiotensin converting enzyme (ACE) inhibitors, imidaprilat and perindoprilat, enhanced the secretion of endogenous HGF, augmented the TNF-α-induced IL-10 secretion and suppressed MCP-1 secretion from AAA tissue. The ACE inhibitors also augmented the expression of HGF in the presence of bradykinin in human aortic endothelial cells in culture (HAECs). In contrast, HGF secretion was not affected by either an angiotensin II type 1 receptor (AT1) antagonist or angiotensin II in AAA tissue or in HAECs. These results suggested that angiotensin converting enzyme inhibitors may be useful in controlling chronic inflammation in AAA, partly due to their enhancement of HGF secretion.