Evaluation of thrombolysis in a porcine model of chronic deep venous thrombosis: an endovascular model

PURPOSE: The advancement of catheter-based interventions for vascular recanalization has underscored the need for an experimental animal model of vascular thrombosis that can be used for the evaluation of interventional therapies. In this model, a porcine model of deep venous thrombosis with a novel endovascular technique was described, and the efficacy of thrombolytic therapy with urokinase was evaluated. METHODS: An endovascular device that consisted of a tapered polytetrafluoroethylene graft attached within a self-expanding nitinol stent was delivered to bilateral common iliac veins in 20 pigs. Venous thrombosis occurred as a result of flow stasis created by the intrastent stenosis. Catheter-directed pulse-spray thrombolysis with urokinase (250,000 units) and heparin (5000 IU) was performed on one limb while the contralateral limb received control saline solution. Thrombolysis was performed in 1 hour (n = 4), 8 hours (n = 4), 3 days (n = 4), 7 days (n = 4), and 14 days (n = 4) after the stent-graft deployment. Venography and intravascular ultrasound were used to evaluate the efficacy of thrombolysis. Light microscopy was used for histologic analysis of the thrombus. RESULTS: Complete thrombolysis was achieved in groups with deep vein thrombosis that were younger than 1 day. Angioplasty of the tapered stent-grafts in the completely thrombolysed iliac vein was successful in restoring venous flow. The efficacy of thrombolysis in 3-day, 7-day, and 14-day groups was 86% +/- 7%, 73% +/- 13%, and 42% +/- 23%, respectively. The thrombolytic efficacy was enhanced to 92% +/- 16% and 86% +/- 18% (P <.05) in 3-day and 7-day groups, respectively, when doses of the pulse-spray thrombolysis were doubled. Increased dosages of the thrombolytic agent, however, did not significantly enhance the thrombus dissolution in the 14-day group. CONCLUSION: The thrombolytic efficacy of urokinase correlated with the chronicity of deep venous thrombosis in our model. An increased dose of urokinase may be used to enhance the efficacy of thrombolysis in a 1-week-old thrombus.     

Rheolytic Pharmacomechanical Thrombectomy in Experimental Chronic Deep Vein Thrombosis: Effect of L-Arginine on Thrombogenicity and Endothelial Vasomotor Function

Purpose Endovascular removal of intravascular thrombus using the AngioJet rheolytic thrombectomy (RT) system has been shown to be clinically effective. This system also permits the concomitant infusion of thrombolytic agent followed by thrombectomy, thus creating a novel strategy known as pharmacomechanical thrombectomy (PMT). Although these interventions have gained wide clinical application, little is known regarding the vessel wall response following thrombectomy therapy. The aims of this study were to assess the effect of thrombectomy interventions on endothelial function in a porcine model of deep venous thrombosis (DVT) and to evaluate the effect of nitric oxide (NO) precursor L-arginine on endothelial function following thrombectomy therapy. Methods Deep vein thrombosis was created in bilateral iliac veins by deploying a self-expanding stent-graft incorporating an intraluminal stenosis from a groin approach. Five pigs underwent sham operation. Following 14 days of DVT, animals were randomized to three groups: the first group received RT treatment (RT group, n = 5); the second group received pharmacomechanical thrombectomy (PMT) with tissue plasminogen activator (alteplase 10 mg; PMT group, n = 5); and the third group received PMT with tPA plus intravenous L-arginine (20 mmol/l) (arginine group, n = 5). Iliac vein patency was evaluated by venography and intravascular ultrasound at 1 week. Nitric oxide level was determined by a chemiluminescent assay of the nitrite/nitrate metabolites (NO_x). Thrombogenicity was evaluated by radiolabeled platelet and fibrin deposition. Veins were harvested and evaluated with light microscopy and scanning electron microscopy (SEM). Endothelial function was evaluated using organ chamber analysis. Results The luminal areas in the sham, RT, PMT, and arginine groups were 34 ± 10 mm², 21 ± 13 mm², 35 ± 18 mm², and 37 ± 16 mm², respectively. All iliac veins remained patent at 2 weeks. No difference in endothelial cell structure was observed between the three treatment groups by means of light microscopic or SEM examination. A decrease in platelet deposition occurred in the arginine group compared to the RT and PMT groups (P < 0.05). The arginine group also showed a greater endothelium-dependent relaxation compared to the RT or PMT groups in response to A23187, bradykinin, and ADP (P < 0.05). Local NO_x level was higher in the arginine group than in the RT or PMT group (2.6 ± 0.6 μmol/l versus 0.3 ± 0.1 μmol/l and 0.3 ± 0.2 μmol/l; P < 0.01). Conclusions AngioJet RT and PMT interventions resulted in similar attenuated endothelium-dependent vasoreactivity and morphologic effect. L-Arginine supplementation preserves endothelial vasoreactivity and reduces platelet deposition following PMT in iliac DVT. Additionally, L-arginine enhances NO production at sites of venous thrombosis. The NO precursor L-arginine may have a therapeutic potential in preserving endothelial function following mechanical thrombectomy. This work was presented at the Molecular Surgeon Symposium on Vascular Injury, Repair and Remodeling at the Baylor College of Medicine, Houston, Texas, May 15 and 16, 2006. The symposium was supported by a grant from the National Institutes of Health (to C. Chen: R13 HL0836500).     

Acute arterial thrombosis causes endothelial dysfunction: a new paradigm for thrombolytic therapy

PURPOSE: The goals of this study were to delineate the time course of endothelial dysfunction after arterial thrombosis, to determine the cause of endothelial dysfunction in this setting, and to determine whether modulating standard thrombolytic therapy would ameliorate the thrombosis-mediated endothelial dysfunction. METHODS: Male adult rats underwent infrarenal aortic occlusion by means of clip ligature to induce arterial thrombosis. After 30 minutes, 1, 2, and 3 hours, ring segments from the infrarenal aorta were harvested and placed into physiologic buffer baths. With the use of a force transducer, both endothelial-dependent relaxation (EDR) and endothelial-independent relaxation (EIR) were measured. Endothelial function and presence were determined by means of factor VIII immunohistochemical staining. Endothelial morphology was evaluated with scanning electron microscopy (SEM). Nitric oxide (NO) levels were determined with a chemiluminescent assay of its nitrite/nitrate metabolites (NO(x)). Standard thrombolytic therapy with urokinase (UK) was infused into thrombosed aortic ring segments and compared with UK supplemented with both low-dose L -arginine (2 mmol) and high-dose L -arginine (20 mmol). RESULTS: Arterial thrombosis decreases EDR. The nadir of EDR occurs 1 hour after thrombosis (mean +/- SE, 13% +/- 6.4% vs 94% +/- 2.6% for controls, P <.005), with persistent lowering of EDR as long as 3 hours after thrombosis. EIR is preserved, and vasoconstriction with norepinephrine or potassium buffer is unaltered. Both endothelial function and presence (n = 6 per group) were documented by means of factor VIII immunohistochemistry. An intact monolayer of endothelium at all time intervals after thrombosis was revealed by means of SEM analysis. No differences between control and thrombosed specimens were revealed by means of the grading of SEM images. Local NO(x) levels were lower after 1 hour of thrombosis, with an increase higher than baseline values at 3 hours. The addition of low-dose L -arginine resulted in a minor increase in EDR. However, high-dose L -arginine resulted in a significant increase in EDR versus controls receiving UK alone (64% +/- 6.3% vs 38% +/- 4.4%, P <.05). Correspondingly, local NO(x) levels were 20-fold higher after the high-dose L -arginine supplementation when compared with UK thrombolysis alone (2.8 +/- 0.52 micromol/L vs 0.133 +/- 0.02 micromol/L, n = 6 samples/group, P <.005). CONCLUSION: Acute arterial thrombosis causes endothelial dysfunction, without causing endothelial cell loss. Endothelial function reaches a nadir after 1 hour of thrombosis. EIR and vasoconstriction remain unaffected, indicating normal smooth muscle cell function. NO(x) levels suggest that NO levels are decreased acutely after thrombosis. Supplementing standard thrombolytic therapy with the NO precursor, l-arginine, ameliorates the endothelial dysfunction seen after acute thrombosis by increasing local NO production.     

Pulse-spray pharmacomechanical thrombolysis for proximal deep vein thrombosis.

OBJECTIVE: The aim of this study was to evaluate the efficacy, safety, and feasibility of pulse-spray pharmacomechanical thrombolysis to treat proximal deep vein thrombosis (DVT) in conjunction with the placement of a non-permanent IVC filter. METHODS: We studied 31 consecutive patients with acute proximal DVT defined as the inferior vena cava (IVC), iliac vein and/or femoral vein, who were diagnosed using duplex ultrasonography and/or contrast venography. All were treated with pulse-spray urokinase. Early success was assessed by comparing the pre- and post-treatment venographic severity score. Non-permanent IVC filters were used to reduce the risk of pulmonary thromboembolism. RESULTS: The average total urokinase dose was 1.71 million IU (range: 0.72-3.6 million IU) and the average duration of therapy was 2.4 days. The average percentage of thrombus lysed was 85% (range: 22-100%). A large thrombus trapped by the filter was detected using cavography before extraction of the filter in one patient. There was no major treatment-related adverse event. CONCLUSION: The combination of pulse-spray pharmacomechanical thrombolysis and the prophylactic use of a non-permanent IVC filter was a safe and effective approach for treating acute proximal DVT.     

The safety,efficacy, and pharmacoeconomics of low-dose alteplase compared with urokinase for catheter-directed thrombolysis of arterial and venous occlusions

PURPOSE: The purpose of this study was to compare the efficacy, complications, and costs associated with low-dose (<2 mg/h) alteplase (tissue plasminogen activator [t-PA]) versus urokinase for the catheter-directed treatment of acute peripheral arterial occlusive disease (PAO) and deep vein thrombosis (DVT). MATERIALS AND METHODS: A retrospective review was performed during sequential time periods on two groups with involved extremities treated with either t-PA with subtherapeutic heparin (TPA group) or urokinase with full heparin (UK group) at a single center. Treatment group characteristics, success rates, complications, dosages, infusion time, and costs were compared. RESULTS: Eighty-nine patients with 93 involved limbs underwent treatment (54 with DVT, 39 with PAO). The treatment groups were statistically identical (TPA: 45 limbs; 24 with DVT, 53.3%; 21 with PAO, 46.7%; UK: 48 limbs; 30 with DVT, 62.5%; 18 with PAO, 37.5%). The overall average hourly infused dose, total dose, infusion time, success rates, and cost of thrombolytic agent were as follows (+/- standard deviation): TPA, 0.86 +/- 0.50 mg/h, 21.2 +/- 15.1 mg, 24.6 +/- 11.2 hours, 89.4%, $466 +/- $331; and UK, 13.5 +/- 5.6 (10(4)) U/h, 4.485 +/- 2.394 million U, 33.3 +/- 13.3 hours, 85.7%, $6871 +/- $3667, respectively. Major and minor complication rates were: TPA, 2.2% and 8.9%; and UK, 2.1% and 10.4%, respectively. No statistical differences in success rates or complications were observed; however, t-PA was significantly (P <.05) less expensive and faster than urokinase. CONCLUSION: Low-dose t-PA combined with subtherapeutic heparin is equally efficacious and safe compared with urokinase. Infusions with t-PA were significantly shorter and less expensive than those with urokinase.     

急性下肢深静脉血栓形成即时溶栓失败的危险因素分析

目的分析急性深静脉血栓形成(deep vein thrombosis,DVT)即时溶栓失败的相关危险因素。方法回顾性分析2015年1月至2018年12月揭阳市人民医院59例行溶栓治疗的急性DVT患者,通过单因素分析和Logistic回归分析分析急性DVT即时溶栓失败的相关危险因素。结果即时溶栓失败率为13.6%。Logistic回归分析结果显示,高龄(>60岁,OR=1.231,95%CI=1.102~1.317)、发病时间>7 d(OR=1.723,95%CI=1.514~1.943)、恶性肿瘤病史(OR=3.447,95%CI=1.791~3.923)和髂静脉压迫综合征(OR=1.272,95%CI=1.153~1.497)是急性DVT即时溶栓失败独立危险因素。结论高龄(>60岁)、发病时间过长(>7 d)、恶性肿瘤病史和髂静脉压迫综合征与急性DVT即时溶栓失败密切相关,是重要的危险因素。     

Oral administration of L-arginine decreases necrosis of the epigastric skin flap in the rat

BACKGROUND: We investigated the effect of prolonged oral arginine administration on tissue necrosis and perfusion in the rat skin flap. METHODS: Twenty-five Sprague-Dawley rats had an 8 x 8 - cm epigastric skin flap elevated and were divided in 2 groups, l-Arginine and Control, which respectively received oral 6% l-arginine solution or water for 8 days postoperatively. On postoperative day 8, area of flap necrosis was measured, and the animals were perfused systemically with 15-microm colored fluorescent microspheres before (blue) and after (yellow-green) ligation of the flap pedicle. RESULTS: l-Arginine reduced total flap necrosis (6.53 +/- 3.76 cm versus 11.91 +/- 4.12 cm; P < 0.01). After pedicle ligation, total flap perfusion remained unchanged in Control but diminished in the l-Arginine group (Control: 0.47 +/- 0.23 and 0.42 +/- 0.06; P = nonsignificant versus l-Arginine: 0.58 +/- 0.29 and 0.27 +/- 0.19; P < 0.01). Serum levels of l-arginine were higher in the l-arginine-treated animals (504 +/- 154 versus 152 +/- 34 micromol/l; P < 0.0001). CONCLUSIONS: Postoperative oral administration of l-arginine decreased flap necrosis in the rat epigastric skin flap. Flap perfusion following oral l-arginine was more dependent on the main vascular pedicle.     

尿激酶联合导管溶栓治疗急性下肢DVT疗效及对相关凝血指标的影响

目的研究尿激酶联合导管溶栓治疗急性下肢DVT临床疗效及其对相关凝血指标的影响。 方法回顾性分析2015年6月至2017年6月收治的52例急性下肢DVT患者,分为导管溶栓组(30例)和系统溶栓组(22例),采用SPSS 21.0统计软件对数据进行分析,血栓溶解率、双侧下肢周径差和凝血指标以( ±s)表示,采用独立t检验;不良反应和临床体征以百分比(%)表示．采用χ²检验,P<0.05表示差异有统计学意义。 结果两组患者术前静脉通畅评分、双侧下肢大小腿周径差、临床症状、凝血指标均无显著差异(P>0.05);导管溶栓组术后静脉通畅评分(8.5±2.0)少于系统溶栓组(12.4±2.9), P＝0.000;血栓溶解率(56.2±26.0)优于系统溶栓组(39.9±23.9),差异有统计学意义(P＝0.011)。导管溶栓组术后双侧大腿中段、小腿中段周径差明显少于系统溶栓组(P<0.05);导管溶栓组术后下肢水肿发生率、下肢疼痛发生率、皮肤色泽改变率等均优于系统溶栓组(P<0.05);导管溶栓组牙龈出血发生率(3.3%)显著少于系统溶栓组(27.3%) ,不良反应总发生率(6.6%)少于系统溶栓组(50.0%),差异有统计学意义(P＝0.001);术后PT、APTT、TT值较系统溶栓组显著升高(P<0.05) ,而FIB值较系统溶栓组显著降低(P<0.05)。 结论尿激酶联合导管溶栓治疗急性下肢DVT较系统溶栓治疗具有更好的临床疗效且不良反应发生率低,对凝血指标影响显著。     

Reduced nitric oxide concentration in the renal cortex of streptozotocin-induced diabetic rats: effects on renal oxygenation and microcirculation

Nitric oxide (NO) regulates vascular tone and mitochondrial respiration. We investigated the hypothesis that there is reduced NO concentration in the renal cortex of diabetic rats that mediates reduced renal cortical blood perfusion and oxygen tension (P O2). Streptozotocin-induced diabetic and control rats were injected with l-arginine followed by Nomega-nitro-L-arginine-metyl-ester (L-NAME). NO and P O2 were measured using microsensors, and local blood flow was recorded by laser-Doppler flowmetry. Plasma arginine and asymmetric dimethylarginine (ADMA) were analyzed by high-performance liquid chromatography. L-Arginine increased cortical NO concentrations more in diabetic animals, whereas changes in blood flow were similar. Cortical P O2 was unaffected by L-arginine in both groups. L-NAME decreased NO in control animals by 87 +/- 15 nmol/l compared with 45 +/- 7 nmol/l in diabetic animals. L-NAME decreased blood perfusion more in diabetic animals, but it only affected P O2 in control animals. Plasma arginine was significantly lower in diabetic animals (79.7 +/- 6.7 vs. 127.9 +/- 3.9 mmol/l), whereas ADMA was unchanged. A larger increase in renal cortical NO concentration after l-arginine injection, a smaller decrease in NO after L-NAME, and reduced plasma arginine suggest substrate limitation for NO formation in the renal cortex of diabetic animals. This demonstrates a new mechanism for diabetes-induced alteration in renal oxygen metabolism and local blood flow regulation.     

合并Cockett综合征的急性下肢深静脉血栓形成患者髂静脉扩张成形时机对导管直接溶栓持续时间的影响

目的探讨合并Cockett综合征的急性下肢深静脉血栓形成（deep vein thrombosis,DVT）患者髂静脉扩张成形时机对导管直接溶栓持续时间的影响。方法回顾性分析38例急性DVT合并Cockett综合征患者的临床资料,根据髂静脉扩张成形和导管直接溶栓的先后顺序,分为导管直接溶栓前扩张髂静脉狭窄（n=14,A组）与导管直接溶栓过程中或溶栓后扩张髂静脉狭窄（n=24,B组）2组,比较溶栓时间、溶栓效果以及扩张局部出血情况。结果A组溶栓时间（25．79±18．23）h,B组（46．83±23．36）h,差异有显著性（t=-2．891,P=0．006）,2组溶栓效果差异无显著性（P〉0．05）。结论介入治疗急性下肢深静脉血栓形成合并Cockett综合征时,髂静脉扩张成形在导管直接溶栓之前实施能够显著缩短溶栓时间,且不增加出血风险。     

Luminal thrombus disrupts nitric oxide-dependent endothelial physiology

BACKGROUND: The goals of this study were: (1) to develop a large animal model to study endothelial function, and (2) to determine if arterial thrombosis induces endothelial dysfunction in vivo. METHODS: Surgical exposure of the porcine iliac and femoral arteries was performed. Normal porcine arteries were compared with arteries subjected to 90 min of arterial thrombosis. External iliac artery (EIA) luminal diameters were measured using M- and B-mode duplex ultrasound. Endothelium-dependent relaxation (EDR) and endothelium-independent relaxation (EIR) were measured using acetylcholine (ACh) and sodium nitroprusside (NTP), respectively. Endothelial integrity was determined by factor VIII immunohistochemistry (F8) and scanning electron microscopy (SEM). Nitric oxide levels were determined using a chemiluminescence assay of nitrite/nitrate metabolites (NO(x)). Continuous variables were analyzed using the two-tailed Student t test. RESULTS: Control artery EDR was 80 +/- 7.1% (+/- SE), while arteries exposed to luminal thrombus for 90 min had an EDR of 55.2 +/- 5.7% (ACh = 15 microg/min, n = 11, P = 0.0231). EIR was preserved in normal and thrombosis groups with uniform response to NTP (4.92 +/- 0.1 cm vs 5.07 +/- 0.42 cm, P = 0.76). F8 staining identified endothelium in all groups. SEM analysis revealed an intact monolayer of endothelium after thrombosis. Local NO(x) levels were 17.3% lower after 90 min of thrombosis (49.3 microM vs 40.8 microM, n = 16, P < 0.001). CONCLUSIONS: Luminal thrombus induces arterial dysfunction acutely without causing endothelial cell loss. EIR remains unaffected, indicating normal smooth muscle cell function. NO(x) levels suggest that nitric oxide levels are decreased acutely after thrombosis. The development of this porcine large animal model allows the in vivo study of vasospasm and alternative thrombolytic regimens.     

Elevated nitric oxide metabolite levels in chronic sinusitis.

Decreased exhaled nitric oxide (NO) is found in chronic sinusitis. NO metabolites (nitrates, nitrites, and S-nitrosothiols) were measured in sinus lavages with a rabbit model of chronic sinusitis. NO metabolite levels (mean +/- SD) were 3.0+/-1.6 micromol/L in uninfected rabbits, 10.7+/-11.4 micromol/L in infected animals, and 7.6+/-5.4 micromol/L in postantrostomy recovering animals. Infected sinuses had elevated levels of NO metabolites that were statistically significant (P<0.01) when compared with uninfected sinuses. Mucociliary transport velocity was measured in uninfected (16.0+/-5.7 mm/minute), infected (5.2+/-1.3 mm/minute), and recovery phases (3.0 mm/minute). Endoscopic appearance, light and electron microscopy, and bacterial cultures improved during recovery. Elevated levels of NO metabolites were found during chronic sinusitis and began to return to normal levels during recovery. The possible link between NO in epithelial autotoxicity and host defense mechanisms warrants further investigation.     

Impaired vasoreactivity despite an increase in plasma nitrite in patients with abdominal aortic aneurysms

OBJECTIVE: This investigation was designed to determine whether differences in vasoreactivity occur in patients with abdominal aortic aneurysms (AAAs) as compared with patients with peripheral arterial occlusive disease (PAOD) or individuals (controls) without known vascular disease. METHODS: Brachial artery vasoreactivity was assessed in a blinded fashion, after endothelium-dependent (ED) and endothelium-independent (EI) flow-mediated vasodilation, in age-matched, male patients with AAAs (n = 11) or PAOD (n = 9) or in controls (n = 10). There were no significant differences in prestudy systolic or diastolic blood pressure, body mass index, or antilipidemic medications among the groups studied. Exclusion criteria included diabetes and tobacco use within 3 months. Quantitative ultrasound scan measurements of brachial artery diameters were performed at rest and after either forearm ischemia (ED) or administration of 0.4 mg sublingual nitroglycerin (EI). Plasma nitric oxide (NO(X) = NO(2) + NO(3)) was measured with the Saville assay. Asymmetric dimethylarginine, an endogenous inhibitor of NO(X) synthase, was measured with liquid chromatography. RESULTS: Initial brachial artery diameters were not significantly different among the groups studied (4.85 +/- 0.18 mm for AAA group, 4.82 +/- 0.17 mm for PAOD group, 4.68 +/- 0.20 mm for controls). ED and EI vasodilation was significantly less (P =.02 and.03, respectively) in the AAA group (-1.71 +/- 1.52 and 8.33 +/- 1.13, respectively) when compared with the controls (2.96 +/- 1.04 and 13.88 +/- 2.16, respectively). However, plasma NO(X) was significantly increased (P =.01) in the AAA group (7.86 +/- 0.85 micromol/L) as compared with both controls (5.13 +/- 0.63 micromol/L) and PAOD (4.85 +/- 0.46 micromol/L). Asymmetric dimethylarginine levels were decreased in the AAA group (0.34 +/- 0.05 micromol/L) as compared with the PAOD group (0.46 +/- 0.09 micromol/L). No correlation existed between aneurysm size and ED or EI vasodilation or plasma NO(X). CONCLUSION: This study is the first to document a divergence between ED and EI vasoreactivity and systemic NO metabolites in patients with AAAs. It is speculated that a dysfunctional vessel wall response, rather than a lack of NO, may be important in the pathogenesis of AAAs.     

Bradykinin preconditions postischemic arterial endothelial function in humans

BACKGROUND: Arterial endothelial dysfunction is an important mechanism of tissue injury caused by ischemia-reperfusion (I/R). Earlier studies of I/R have shown that intracoronary preinfusion with 2.5-5 microg/mL bradykinin (BK) could alleviate the postischemic myocardial damage. Using an experimental human model of I/R, we investigated whether preceding infusion with BK could prevent the I/R-induced arterial endothelial dysfunction. METHODS: The left radial artery (LRA) from 16 healthy male adults, 18 to 30 years old, was submitted to I/R by completely occluding the left brachial artery with a pressure tourniquet for 20 minutes (ischemia), followed by its release (reperfusion). Prior to I/R, half of the subjects were randomly assigned to receive either BK (5 microg/mL) or saline, both being infused into the left brachial artery (0.5 mL/min, 10 min). The infusion was followed by a 10-minute drug-free period. The endothelial function of the LRA was studied by measuring the flow-mediated dilation (FMD) at baseline (prior to drug infusion), and at 15 minutes of reperfusion. In addition, baseline radial artery diameter, plasma nitrate, and von Willebrand factor were measured at these time points, and immediately before I/R (pre-I/R). RESULTS: BK had no effect on the pre-I/R plasma nitrate (p > 0.5 vs. saline) and diameter of LRA (p > 0.5 vs. baseline). At 15 minutes of reperfusion, FMD was significantly decreased in the saline group as compared to baseline (absolute dilation: 0.08 +/- 0.03 vs. 3.02 +/- 0.8 mm, respectively, p < 0.01; percentage dilation: 3 +/- 0.6 vs. 8 +/- 0.6%, respectively, p < 0.001), but it remained unaffected in the BK group (absolute dilation: 3.06 +/- 0.9 vs. 3.27 +/- 0.8 mm, respectively, p > 0.5; percentage dilation: 7 +/- 0.7 vs. 8 +/- 0.8%, respectively, p > 0.5). A similar trend was observed with regard to plasma nitrate, which remained unchanged in the BK group (37.01 +/- 4.14 vs. 39.14 +/- 4.49 micromol/L, p > 0.5) but decreased in the saline group (35.91 +/- 3.03 vs. 28.91 +/- 2.81 micromol/L, p < 0.1). CONCLUSION: Infusion of BK could protect the arterial endothelial function against I/R injury in humans, possibly in part by preserving the endothelial NO availability. The findings support the use of BK in the prevention of tissue injury due to I/R and might reveal an additional mechanism whereby ACE inhibitors exert their preconditioning effects on myocardium.     

Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy

OBJECTIVE: Ischemic heart failure is an increasingly prevalent global health concern with major morbidity and mortality. Currently, therapies are limited, and novel revascularization methods might have a role. This study examined enhancing endogenous myocardial revascularization by expanding bone marrow-derived endothelial progenitor cells with the marrow stimulant granulocyte-monocyte colony-stimulating factor and recruiting the endothelial progenitor cells with intramyocardial administration of the potent endothelial progenitor cell chemokine stromal cell-derived factor. METHODS: Ischemic cardiomyopathy was induced in Lewis rats (n = 40) through left anterior descending coronary artery ligation. After 3 weeks, animals were randomized into 4 groups: saline control, granulocyte-monocyte colony-stimulating factor only (GM-CSF only), stromal cell-derived factor only (SDF only), and combined stromal cell-derived factor/granulocyte-monocyte colony-stimulating factor (SDF/GM-CSF) (n = 10 each). After another 3 weeks, hearts were analyzed for endothelial progenitor cell density by endothelial progenitor cell marker colocalization immunohistochemistry, vasculogenesis by von Willebrand immunohistochemistry, ventricular geometry by hematoxylin-and-eosin microscopy, and in vivo myocardial function with an intracavitary pressure-volume conductance microcatheter. RESULTS: The saline control, GM-CSF only, and SDF only groups were equivalent. Compared with the saline control group, animals in the SDF/GM-CSF group exhibited increased endothelial progenitor cell density (21.7 +/- 3.2 vs 9.6 +/- 3.1 CD34 + /vascular endothelial growth factor receptor 2-positive cells per high-power field, P = .01). There was enhanced vascularity (44.1 +/- 5.5 versus 23.8 +/- 2.2 von Willebrand factor-positive vessels per high-power field, P = .007). SDF/GM-CSF group animals experienced less adverse ventricular remodeling, as manifested by less cavitary dilatation (9.8 +/- 0.1 mm vs 10.1 +/- 0.1 mm [control], P = .04) and increased border-zone wall thickness (1.78 +/- 0.19 vs 1.41 +/- 0.16 mm [control], P = .03). (SDF/GM-CSF group animals had improved cardiac function compared with animals in the saline control group (maximum pressure: 93.9 +/- 3.2 vs 71.7 +/- 3.1 mm Hg, P < .001; maximum dP/dt: 3513 +/- 303 vs 2602 +/- 201 mm Hg/s, P < .05; cardiac output: 21.3 +/- 2.7 vs 13.3 +/- 1.3 mL/min, P < .01; end-systolic pressure-volume relationship slope: 1.7 +/- 0.4 vs 0.5 +/- 0.2 mm Hg/microL, P < .01.) CONCLUSION: This novel revascularization strategy of bone marrow stimulation and intramyocardial delivery of the endothelial progenitor cell chemokine stromal cell-derived factor yielded significantly enhanced myocardial endothelial progenitor cell density, vasculogenesis, geometric preservation, and contractility in a model of ischemic cardiomyopathy.     

经导管直接溶栓治疗下肢深静脉血栓形成的尿激酶量效分析

目的探讨经导管直接溶栓（CDT）治疗下肢深静脉血栓中尿激酶的合理用量。方法将拟接受CDT的90例DVT患者随机分为3组：A组用小剂量尿激酶溶栓（每日用量〈40万U）,B组用中等剂量（每日用量40万～80万U）,C组用大剂量（每日用量〉80万U）进行溶栓治疗。比较3组的溶栓效果、溶栓时间及出血情况。结果3组溶栓疗效差异有统计学意义（Hc=15．09,P〈O．05）,A组与B组疗效差异有统计学意义（t=1．99,P〈0．05）。3组溶栓时间差异有统计学意义（F=4．92,P〈0．05）。各组出血发生率差异无统计学意义（x^2=2．96,P〉0．05）,C组出血程度最重。结论CDT治疗DVT安全有效,每日尿激酶用量在40万U～80万U时溶栓疗效好,且出血发生率低。     

胃肠道左旋精氨酸营养干预对严重烧伤患者休克期复苏的影响

目的观察严重烧伤患者休克期经胃肠道给予左旋(L)精氨酸对休克复苏的影响,探讨其机制。方法选取烧伤面积≥30%TBSA的患者20例,并随机分为:L-精氨酸组,伤后24h内开始从鼻肠管给予L-精氨酸;对照组,伤后24h内开始从鼻肠管给予50g/L葡萄糖盐水500ml/d,连续4d,每组10例。在伤后1、2、3、4d分别抽取两组患者静脉血,检测其血清超氧化物歧化酶(SOD)活性及丙二醛(MDA)和一氧化氮(NO)含量,并抽取患者动脉血检测其乳酸含量。结果L-精氨酸组患者SOD活性在伤后呈上升趋势,于伤后4d达峰值(68±23)U/ml,与对照组(31±9)U/ml比较,差异有统计学意义(P<0·01)。两组患者伤后MDA、NO含量均呈下降趋势,伤后2dL-精氨酸组NO[(50±14)μmol/L]下降最明显,与对照组(78±22)μmol/L比较,差异有统计学意义(P<0.01)。伤后4d两组患者MDA下降最明显[(3.4±0.8)、(3.5±1.3)μmol/L],L-精氨酸组血乳酸含量在伤后2、3d显著低于对照组(P<0.05或0.01)。结论严重烧伤患者休克期经胃肠道给予L-精氨酸可抑制其体内NO含量过度升高,使血乳酸含量降低,血清SOD活性增加,改善组织脏器血流灌注及氧合状态,减轻缺血再灌注损伤,有利于预防隐性休克的发生或减轻其损害。     

Catheter-directed therapy for DVT after pancreas transplantation

INTRODUCTION: Iliac vein deep venous thrombosis (DVT) ipsilateral to the pancreas transplant can lead to severe leg edema and compromise graft function. Treatment modalities for iliac vein DVT in the pancreas transplant recipient are limited. METHODS: Medical records of patients receiving pancreas transplants at a single center from November 1989 to July 2003 were reviewed retrospectively, identifying patients with iliac vein DVT. There were 287 pancreas transplants performed during this time. Pancreas transplantation in all recipients was performed in the right iliac fossa with the arterial supply consisting of a donor iliac artery Y interposition graft. Systemic venous drainage was to the iliac vein. Exocrine drainage was enteric or to the bladder. RESULTS: Four (1.4%) cases of iliac DVT were identified. All patients manifested lower extremity edema ipsilateral to the pancreas transplant. DVT was detected by ultrasound on days 4, 5, 13, and 60 post-transplant. In all cases, the iliac vein caudad to the pancreatic venous anastomosis was noted to be stenotic. Management involved balloon dilatation and endovascular stent placement in one patient, thrombolysis with tissue plasma antigen (t-PA) followed by stent placement in one patient, and percutaneous mechanical thrombectomy in two patients. All patients had improvement in leg edema and two patients continue to have good pancreatic allograft function. CONCLUSIONS: Iliac DVT is a rare complication of pancreas transplantation that usually develops in an area of stenosis caudad to the pancreatic venous anastomosis. Catheter-based treatment modalities with use of endovascular stents for treatment of underlying stenoses can serve as an adjunct in treating these complications.     

A comparison of human recombinant tissue-type plasminogen activator and urokinase in microsurgical thrombolysis in the rat

A comparison was made between several characteristics of tissue-type plasminogen activator (t-PA) and urokinase (UK), potentially useful in microsurgery to restore perfusion to ischemic free-tissue transfers. An intraarterial infusion of one of the drugs (or normal saline [NS] as a control) was performed in conjunction with a rat femoral vein clot model. Both t-PA and urokinase were effective in lysing 100 percent of the venous clots on the side of infusion. This occurred in only 25 percent of controls (p = .0035). Thrombolysis on the contralateral side, a measure of systemic effect, occurred in 38 percent, 50 percent, and 13 percent of veins using t-PA, UK, and NS, respectively (t-PA vs. UK p = 1.0, t-PA vs. NS p = .28, UK vs. NS p = .14). Rethrombosis occurred in 13 percent and 25 percent of ipsilateral veins treated with t-PA and urokinase, respectively, and in one of the two veins that had resumed flow during saline infusion (t-PA vs. UK p = .30) Scanning electron microscopy was performed 4 hr and 48 hr after thrombolysis. No differences between thrombolytic agents was noted in terms of residual thrombus and vessel characteristics. The data suggest that t-PA and urokinase are effective, with no clear advantage of one agent over the other.     

Experimental treatment of thrombotic vascular occlusion

The role of laser energy in the treatment of thrombotic vascular occlusion was evaluated in two sets of experiments. First, 10 polytetrafluoroethylene grafts were used to replace segments of the superficial femoral arteries in dogs and were thrombosed by distal ligation. Occlusion was maintained for one hour, or for 7, 14, 21, and 28 days in each of two grafts. Patency was restored in all 10 grafts without perforation or anastomotic disruption using a 2 mm hot tip probe powered by an Argon laser. However, increased organization of thrombus related to the duration of occlusion lead to decreased laser channel diameters, and 75% of the 28 day thrombus remained in the graft after recanalization. The second experiments tested the added benefit of thrombolytic infusion following laser recanalization. Bilateral external iliac artery thrombosis was induced in dogs by operative vessel isolation, de-endothelialization, and thrombin injection. At 7 days the efficacy of laser-assisted thrombolysis (LAT) versus enzymatic thrombolysis (ET) alone was compared. Eight vessels underwent ET by urokinase (4000 I.U./min.); 14 vessels were laser recanalized prior to thrombolytic infusion. LAT was performed from a carotid artery approach in 8 vessels (antegrade) and from a femoral artery in 6 vessels (retrograde). In contrast to studies using the hot tip alone, both ET and LAT accomplished complete thrombus removal. However, LAT lead to significant iliac arterial flow in 9 +/- 8 min. (antegrade) and 25 +/- 8 min. (retrograde) while ET required 109 +/- 47 min (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)