Endothelial Dysfunction, Increased Arterial Stiffness, and Cardiovascular Risk Prediction in Patients With Coronary Artery Disease: FMD‐J (Flow‐Mediated Dilation Japan) Study A

BackgroundThe usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known.Methods and ResultsWe measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed.ConclusionsIn patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification

FMD, PWV, and Cardiovascular Events

Background The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. Methods and Results We measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. Conclusions In patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification

上部消化管の潰瘍性出血に対するフィブリン接着剤局注による止血の実験的研究 : エタノールとの比較

2000年以来,フィブリン接着剤(FG)の局注による内視鏡的止血を検討してきたが,クリッピング,エタノール(E)局注の実施し難い上部消化管の止血に対して満足しうる結果が得られた.これまで上部消化管の潰瘍性出血に対するFG局注による内視鏡的止血についてはかなりの報告がみられるが,多くは臨床例についての報告であり,その病理組織学的検討についての報告は殆ど見当たらない.ここではラットを用いて,実験的に上部消化管の潰瘍性出血を作製し,これに対するFG局注の効果と有効性について病理組織学的にE局注と比較しながら検討した.S-Dラットをエーテル麻酔下に開腹し,胃切開の後,胃幽門前庭部に機械的に出血性潰瘍を作製した.FGあるいはEを潰瘍部に局注した後,外科創を縫合した.その1,3,あるいは5日後に胃を摘出し病理組織学的に検討した.E群ではcontrol群(生理食塩水局注)と比較して止血効果を確認したが,組織傷害は増強し,炎症細胞の浸潤が局注後数日間増加する像がみられた.FG群の止血効果はE群とほぼ同等であったが,組織傷害は限られた徴候がみられたのみで,E群よりも軽度であった.E群では胃壁の穿孔例がみられたが,FG群およびcontrol群では穿孔例はなかった.E群と比較してFG群は組織刺激性ないし傷害が少なく,潰瘍を増悪することもなく,組織に長時間停留して作用が持続的であった.以上よりFG局注は有効な止血法であり,上記利点をもつ内視鏡的止血法として加えうるものと考える.Since 2000, we have been conducting studies on endoscopic hemostasis with local injection of fibrin glue (FG). The procedure has produced satisfactory results in treating patients with hemorrhage of the upper digestive tract who were difficult to treat with more conventional method, such as clipping or ethanol injection. There have been no reports on the histopathological effects of FG. In this study, the effects and efficacy of locally injected FG were investigated by using rats and the result was compared with the effects of ethanol (E). Sprague-Dawley rats were subjected to a laparotomy under ether anesthesia, followed by mechanical creation of a hemorrhagic ulcer at the pyloric vestibulum. In group E, in comparison with the control group, a hemostatic effect was recognized; but tissue damage was intensified and infiltration by inflammatory cells increased during the several days following the procedure. In group FG, the hemostatic effect was almost comparable to that of group E and there were only limited signs of tissue damage, which were much milder than in group E. In the latter group, the development of a postoperative perforation was observed, whereas no animals in the sham or group FG experienced similar conditions. Compared with E, local injection of FG may be a practical procedure for endoscopic hemostasis

上部消化管の潰瘍性出血に対するフィブリン接着剤局注による止血の実験的研究 : エタノールとの比較

2000年以来,フィブリン接着剤(FG)の局注による内視鏡的止血を検討してきたが,クリッピング,エタノール(E)局注の実施し難い上部消化管の止血に対して満足しうる結果が得られた.これまで上部消化管の潰瘍性出血に対するFG局注による内視鏡的止血についてはかなりの報告がみられるが,多くは臨床例についての報告であり,その病理組織学的検討についての報告は殆ど見当たらない.ここではラットを用いて,実験的に上部消化管の潰瘍性出血を作製し,これに対するFG局注の効果と有効性について病理組織学的にE局注と比較しながら検討した.S-Dラットをエーテル麻酔下に開腹し,胃切開の後,胃幽門前庭部に機械的に出血性潰瘍を作製した.FGあるいはEを潰瘍部に局注した後,外科創を縫合した.その1,3,あるいは5日後に胃を摘出し病理組織学的に検討した.E群ではcontrol群(生理食塩水局注)と比較して止血効果を確認したが,組織傷害は増強し,炎症細胞の浸潤が局注後数日間増加する像がみられた.FG群の止血効果はE群とほぼ同等であったが,組織傷害は限られた徴候がみられたのみで,E群よりも軽度であった.E群では胃壁の穿孔例がみられたが,FG群およびcontrol群では穿孔例はなかった.E群と比較してFG群は組織刺激性ないし傷害が少なく,潰瘍を増悪することもなく,組織に長時間停留して作用が持続的であった.以上よりFG局注は有効な止血法であり,上記利点をもつ内視鏡的止血法として加えうるものと考える.Since 2000, we have been conducting studies on endoscopic hemostasis with local injection of fibrin glue (FG). The procedure has produced satisfactory results in treating patients with hemorrhage of the upper digestive tract who were difficult to treat with more conventional method, such as clipping or ethanol injection. There have been no reports on the histopathological effects of FG. In this study, the effects and efficacy of locally injected FG were investigated by using rats and the result was compared with the effects of ethanol (E). Sprague-Dawley rats were subjected to a laparotomy under ether anesthesia, followed by mechanical creation of a hemorrhagic ulcer at the pyloric vestibulum. In group E, in comparison with the control group, a hemostatic effect was recognized; but tissue damage was intensified and infiltration by inflammatory cells increased during the several days following the procedure. In group FG, the hemostatic effect was almost comparable to that of group E and there were only limited signs of tissue damage, which were much milder than in group E. In the latter group, the development of a postoperative perforation was observed, whereas no animals in the sham or group FG experienced similar conditions. Compared with E, local injection of FG may be a practical procedure for endoscopic hemostasis

敗血症性ショックに対する各種の一酸化窒素合成酵素阻害剤の治療効果 : 血行動態および組織病理学的変化に対する影響

敗血症性ショックに対する一酸化窒素合成酵素(NOS)阻害剤の治療効果を,血行動態,組織における一酸化窒素(NO)産生,凝固線溶系および組織病理学的変化に対する影響について検討した.エンドトキシンショックに対するNOS阻害剤の昇圧効果はドブタミン(DOB)の昇圧効果と比較検討した.ペントバルビタール麻酔ラットを用い,エンドトキシン(5mg/kg iv)適用によりショックを発生させた.NOS阻害剤としては,非選択的NOS阻害剤N^G-monomethyl-L-arginine (L-NMMA),相対的誘導型NOS(iNOS)阻害剤S-methylisothiourea (SMT)およびiNOSに親和性のより高いONO-1714を用いた.エンドトキシンの静脈内適用により,初期にはNO産生は認められず,1～2時間後より徐々にNO産生がみられるようになり,4～6時間後にピークとなり,血圧はショック状態となった.この時NOS阻害剤あるいはDOBを投与すると,SMTおよびONO-1714では顕著な低血圧の改善がみられたが,L-NMMAの作用は軽度であり,DOBでは有意な血圧の変化はみられなかった.エンドトキシン適用により,組織病理学的変化として腎,肺,肝および小腸について検討したが,組織の出血,浮腫,壊死および血管内微小血栓が認められ,これらはNOS阻害剤の投与により,改善はみられず,却って一部組織像の増悪がみられた.エンドトキシンショック時のNOの増加による低血圧はNOS阻害剤によるNOの除去により改善されるが,侵襲時のサイトカイン放出による組織因子の遊離および白血球の活性化を介する組織傷害は,NOS-NO系と関係なく,NOS阻害剤の影響を受けず,却ってNOの除去は組織因子等の作用を増強して,組織像の一部増悪がみられたと考える.敗血症性ショックに対するNOS阻害剤による治療に際して,この組織傷害性への対処の検討が必要であると考える.The effects of nitric oxide synthase (NOS) inhibitors were investigated on the hemodynamics, nitric oxide (NO) production, coagulofibrinolytic system and histopathological changes to prove their therapeutic efficacy in septic shock. Their hypertensive effects were compared with those of dobutamine (DOB). Rats under pentobarbital anesthesia were treated with endotoxin (5 mg/kg i.v.) to produce endotoxin shock. The NOS inhibitors used were: N^G-monomethyl-L-arginine (L-NMMA, a non-selective NOS inhibitor), S-methylisothiourea (SMT, a relatively selective inducible NOS inhibitor or iNOS), and ONO-1714 (a more selective iNOS inhibitor). Following an early quiescent state, NO production began gradually 1 to 2 hr after endotoxin administration and peaked in 4 to 6 hr resulting in hypotensive shock. Administering NOS inhibitors or DOB during the shock stage produced a marked amelioration of hypotension with SMT or ONO-1714, a slight improvement with L-NMMA, and no significant change with DOB. After endotoxin administration, the kidney, lung, liver, and small intestine, examined for histopathological changes, showed hemorrhage, edema, necrosis, and intravascular microthrombosis. The NOS inhibitors failed to correct these conditions, even exacerbating in some (a mechanism for the actions involved was discussed). The tissue damage and its treatment should be investigated further when NOS inhibitors are used to treat septic shock