Masayoshi Nishimoto

Increased local angiotensin II formation in aneurysmal aorta.

We investigated the levels and locations of angiotensin II-forming enzymes, angiotensin converting enzyme (ACE) and chymase, in aneurysmal and normal aortas. Aneurysmal aortic specimens (n = 14) were obtained at the time of operative aneurysm repair from 14 patients ranging in age from 57 to 84 y. Normal aortic specimens (n = 16) were obtained from 16 patients (48 to 72 y) who underwent coronary artery bypass surgery. The ACE and chymase activities were determined using each specimen. Sections of each specimen were immunostained with antibodies for ACE and chymase. The ACE activities in the aneurysmal and normal aortas were 0.82 +/- 0.10 and 0.14 +/- 0.05 mU/mg protein, respectively, and this difference was significant. The chymase activities in the aneurysmal and normal aortas were 17.9 +/- 2.40 and 1.02 +/- 0.18 mU/mg protein, respectively, and this difference was also significant. In the aneurysmal aorta, ACE-positive cells were detected with macrophages in the intima and media and chymase-positive cells were detected with mast cells in the media and adventitia, whereas positive ACE and chymase cells in the normal aorta were located only in the endothelium and adventitia, respectively. Angiotensin II-forming enzymes, chymase and ACE, were significantly increased in the aneurysmal aorta, and increased angiotensin II may be associated with the development of aneurysmal formations.

Inhibition of chymase reduces vascular proliferation in dog grafted veins

We investigated the effect of a chymase inhibitor Suc‐Val‐Pro‐PheP(OPh)2 on the proliferation of the grafted vein in dog. By 28 days after the operation, the mean intimal area of the grafted vein in the placebo group was 3.24±0.32 mm2. The intimal area of the grafted vein in the chymase inhibitor‐treated group was reduced to 63.9%. In the placebo group, the activities of chymase and angiotensin‐converting enzyme in grafted vein were significantly increased 15‐ and 2‐fold, respectively. In the chymase inhibitor‐treated group, chymase activity in the grafted veins was decreased significantly. These findings suggest that inhibition of chymase appears useful for preventing vascular proliferation.

Oral administration of a specific chymase inhibitor, NK3201, inhibits vascular proliferation in grafted vein.

Chymase may play an important role in vascular proliferation, as shown by in-vitro experiments, but the role of chymase in vivo has been unclear. In this study, we investigated the effect of a novel chymase inhibitor, NK3201, on this proliferation in dog grafted veins. NK3201 inhibited human and dog chymases, but not rabbit ACE. NK3201 suppressed the Ang I-induced vascular contraction in isolated dog arteries in the presence of an ACE inhibitor, and the IC50 value of chymostatin and NK3201 in dog artery was 320 nM. In dog, the concentration of NK3201 in blood was about 10 microM at 24 h after oral administration of the drug (5 mg/kg). In the group treated with NK3201, each dog was administered orally 5 mg/kg per day from 5 days before to the day before the removal of the grafted veins. Each dog underwent right common carotid artery bypass grafting with the ipsilaterial external jugular vein. By 28 days after grafting, a significant vascular proliferation was observed in the grafted veins and the chymase activity was also increased significantly. Treatment with chymase inhibitor significantly suppressed the proliferation of the grafted veins and the increased chymase activity. In this study, we demonstrate for the first time that oral administration of a specific chymase inhibitor, NK3201, appears useful for preventing vascular proliferation.

The significance of chymase in the progression of abdominal aortic aneurysms in dogs.

In this study, we investigated the effect of a specific chymase inhibitor, NK3201, in the progression of abdominal aortic aneurysm in a dog experimental model. Abdominal aortic aneurysms were induced in dogs by injecting elastase into the abdominal aorta. NK3201 (1 mg/kg per day, p.o.) or a placebo was started 3 days before elastase injection and continued for 8 weeks after the injection. On abdominal ultrasound, the aortic diameter was seen to gradually expand in the placebo-treated group, but not in the NK3201-treated group. Eight weeks after elastase injection, the ratio of the medial area to the total area in the placebo-treated group was significantly smaller than that in the normal group, but it was significantly larger than that in the NK3201-treated group. In addition to chymase activity, angiotensin II–forming and matrix metalloproteinase-9 activities were significantly higher in the placebo-treated group than in the normal group; in the NK3201-treated group, all of these activities were significantly decreased. On immunohistochemical analyses, there was a significantly greater number of chymase-positive cells in the placebo-treated group than in the normal group, but the number was significantly smaller in the NK3201-treated group than in the placebo-treated group. Thus, chymase inhibition may become a useful strategy for preventing abdominal aortic aneurysms.

Angiotensin II receptor antagonist, L-158,809, prevents intimal hyperplasia in dog grafted veins.

We investigated the levels of the angiotensin II-forming enzymes, chymase and angiotensin converting enzyme (ACE), in dog grafted veins, and studied the effect of an angiotensin II type 1 receptor antagonist, L-158,809, on vascular proliferation in the grafted veins. The right external jugular vein was grafted to the ipsilaterial carotid artery. In the group treated with L-158,809, the drug (10 mg/kg per day, p.o.) were administered orally from 7 days before the operation to 28 days after it, while the others were administrated placebo. In the placebo-treated group, the chymase activity in the grafted veins was increased about 10-fold and the ACE activity was doubled. The areas of intima and media were significantly increased in the grafted veins in the placebo-treated group. L-158,809 significantly reduced the intimal area of the grafted veins. An angiotensin II receptor antagonist, L-158,809, prevented the vascular proliferation in the grafted veins, and the development of the proliferation may depend on activation of local angiotensin II formation.

Surgical treatment of traumatic thoracic aorta rupture: a 7-year experience.

OBJECTIVES Traumatic aortic rupture is highly lethal and an ongoing therapeutic challenge. We review our 7-year experience with traumatic aortic disruption. METHODS We treated 12 cases of traumatic rupture of the thoracic aorta (TRTA) from December 1994 to June 2001 at our institution. Of these, 9 were male, and the average age 26 years. Injuries were caused by traffic accidents in 9 cases and falls in 3. Contrast-enhanced helical computed tomography was used to diagnose10 cases and digital subtraction angiography to diagnose 2 at other hospitals. Six of 12 (50%) disruptions were located in the aortic isthms. All surgery was conducted under cardiopulmonary bypass. A percutaneous cardiopulmonary support system (heparin-bonded artificial lung and centrifugal pump) was used in 6 cases since 1998. RESULTS Among the 12 patients, 6 had early surgical repair within 2 days after the accident, and all survived free of neurological problems. Six other had repair delayed more than 2 days and all were doing well. CONCLUSION Immediate repair of aortic lesions should be the rule because the majority of deaths from TRTA occur within 24 hours. We believe, however, that immediate surgery may not be necessary for some patients with severe, multiple associated lesions who survive initial traumatic aortic disruption of the aorta.

Cilostazol suppresses intimal formation in dog grafted veins with reduction of angiotensin II-forming enzymes

Cilostazol prevents neointimal formation, but its mechanism has remained unclear. We investigated whether intimal formation in dog grafted veins is suppressed by cilostazol, and studied the effect of cilostazol on angiotensin II-forming enzymes. The external jugular vein was grafted to the carotid artery, and cilostazol (60 mg/kg/day) was administered orally. By 28 days after the surgery, the intimal cross-sectional area of the grafted vein was reduced to 16.7% by treatment of cilostazol, and the activities of angiotensin II-forming enzymes were suppressed significantly. The inhibitory effect of cilostazol in intimal formation may be dependent on inhibition of angiotensin II-forming enzymes.

Successful Treatment of an Aortoesophageal Fistula after Open Stent Grafting of a Right Aortic Arch and a Descending Aortic Aneurysm Rupture

症例は52歳,男性.呼吸困難を主訴に他院に救急搬送された.緊急気管挿管下にCTを施行したところ,右側大動脈弓を認め弓部に気管と食道の後方で左方に突出する最大径約10cmの大動脈瘤が存在し,また,縦隔内血腫を伴っており,破裂の判断で当センター搬送とされた.降圧と鎮静下に解剖学的検討を十分に行い,来院後5日目に手術を行った.胸骨正中切開で到達し,超低体温循環停止下に右鎖骨下動脈末梢側を切開し,open stent法により直径34mm,長さ15cmのstent graftを留置,中枢側吻合後,左鎖骨下動脈を非解剖学的に再建した.経過は良好であったが,第12病日に突然の発熱,CT,食道造影で大動脈食道瘻が確認された.抗生剤で感染コントロールを十分に行い,初回術後26日に食道亜全摘術+食道胃管吻合+瘤内大網充填術を行った.これにより感染は制御され,初回術後73日に転院,術後1年半の現在感染徴候なく社会復帰している.

A Successful Case of Open Stent-Grafting for an Impending Ruptured Acute Type B Aortic Dissection

症例は70歳,男性,突然の胸背部痛を自覚した.胸部造影CTにおいて偽腔閉塞型急性B型解離を認め保存的安静降圧加療を行った.第5病日,突然の呼吸困難が自覚され,胸部造影CTにおいて肺動脈血栓塞栓症を診断し,抗凝固療法を開始した.第16病日,再び胸背部痛が自覚され,胸部造影CTにおいて瘤径および残存するULP (ulcer like projection)の急速な拡大を認め切迫破裂と判断し,open stent法による緊急手術を施行した.術後経過良好で,合併症なく軽快退院となった.急性B型解離の切迫破裂に対し,本術式は従来法と比べて低侵襲で有用な方法と考えられた.

Prognosis of Stanford Type B Acute Aortic Dissection and Availability of Early Rehabilitation Program in Medical Treatment.

Stanford B型急性大動脈解離90例の治療成績と保存療法における早期離床の有用性について検討した.90例中の破裂は来院時破裂11例,入院後破裂1例の計12例(13.3%)であった.このうち8例に手術を行い死亡は1例(12.5%)であった.来院時非破裂例79例に保存療法を行った.保存療法中の破裂は1例(1.3%)で,死亡は破裂1例と腹部臓器壊死2例の計3例(死亡率3.8%)であった.来院時破裂例も含めたB型全体の死亡は90例中6例(6.7%)であった.偽腔閉鎖例の死亡は1例のみで,合併症頻度も開存例より少なかった.1週間で立位,2週間で自由歩行とする早期離床プログラムを作成し最近の31例に用いた.早期離床例に破裂例はなく,肺炎や薬剤を要する不穏などの合併症は有意に減少した.破裂例を除けばB型解離の保存療法の成績は良好で,降圧療法を厳密に行ったうえでの早期離床は合併症減少にも役立った.