Real-Time Assessment of Tissue Oxygen Saturation Using a Novel Oximeter During Revascularization for Acute Limb Ischemia: A Case Report.

Emergency surgery was performed to treat acute lower limb ischemia caused by heart thromboembolism and concomitant popliteal artery aneurysm. Using a near-infrared spectroscopy oximeter, regional tissue oxygen saturation (rSO2) was monitored to assess the tissue perfusion pre-, intra-, and postoperatively. rSO2 values did not increase sufficiently following thromboembolectomy of the superficial femoral artery, but they dramatically recovered after additional popliteal-anterior tibial bypass surgery. The affected limb was successfully salvaged. rSO2 monitoring was easily measured intraoperatively, which might be beneficial in evaluating tissue perfusion in patients with acute limb ischemia.

Survey of Food Intake in Patients with Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a vascular disease that involves asymptomatic progressive expansion of the abdominal aorta. Aneurysm rupture is associated with a high mortality rate. Dietary conditions may be associated with the development and rupture of AAA. However, the relationship between nutrition and AAA is not completely understood. In this study, a nutrition survey was conducted using a brief self-administered diet history questionnaire (BDHQ) to evaluate the relationship between AAA and dietary habits. One-hundred and twenty-six Japanese people participated in the nutrition survey. Food intake status was analyzed in four groups: the analyzed group-1 (all men), analyzed group-2 (men with smoking history), analyzed group-3 (all women) and analyzed group-4 (women without smoking history). In group-2 and group-3, the intake of citrus fruits was significantly lower in the AAA group than in the non-AAA group. In group-2, the intake of soybean and soybean products was significantly lower in the AAA group than in the non-AAA group. In analyzed group-3, the intake of other vegetables (vegetables except for green and yellow vegetables and soybeans) and seafood was significantly lower in the AAA group than in the non-AAA group. This study suggests that AAA onset may be associated with low intake of fruits, soybeans, vegetables, and seafood.

Characteristics and Prognostic Factors of Venous Thromboembolism in Cancer Patients.

Background: Improving the prognosis of patients with malignant tumors is increasing the number of patients who develop venous thromboembolism. We examined the characteristics and prognostic factors of VTE patients with cancer. Methods: We diagnosed 725 VTE patients from April 2005 to March 2018. There were 322 cancer associated patients (CAT) and 403 non-cancer associated patients (nonCAT). We examined characteristics and prognostic factors of VTE in CAT patients. Results: There were 156 women and 166 men in CAT, and 132 women and 271 men in nonCAT. There was no significant difference in the location of proximal portion of thrombus. When locations were divided into left leg, right leg, and bilateral legs, bilateral cases were more common in CAT group. Comparing the overall survival after VTE diagnosis in the CAT group, the prognosis was poor in patients with high D-dimer level (≧6 µg/mL) along with cancer metastasis and recurrence. Conclusions: Various VTE factors predict prognosis in CAT patients, and CAT is important in the treatment of cancer patients. (This is secondary publication from Jpn J Phlebol 2020; 31(3): 153-159.).

The Patency of Tibial/Peroneal Arteries Affects the Increment of Regional Tissue Saturation of Oxygen in Each Angiosome after Superficial Femoral Artery Revascularization.

Objective: The angiosome model is a controversial concept in the revascularization of patients with chronic limb-threatening ischemia (CLTI). The aim of this study was to demonstrate the importance of patency of the tibial/peroneal arteries for regional tissue oxygenation in each angiosome during endovascular therapy (EVT) of the superficial femoral artery (SFA). Materials and Methods: We devised a novel near-infrared spectroscopy oximeter, "TOE-20," for real-time monitoring of regional tissue oxygen saturation (rSO2). Using TOE-20, we prospectively assessed rSO2 at each angiosome in 23 CLTI patients who underwent successful revascularization of the SFA. During EVT, three sensor probes were placed at the dorsal foot, plantar foot, and outer ankle for rSO2 monitoring. Results: At the end of EVT, rSO2 at all angiosomes was significantly elevated by SFA revascularization. The change in rSO2 in each angiosome was larger in patients with patent relevant arteries than in those with occluded relevant arteries (i.e., anterior tibial artery patency, posterior tibial artery patency, and peroneal artery patency). Conclusion: The patency of the tibial/peroneal arteries is important for regional tissue oxygenation in EVT. Using TOE-20 and rSO2-based revascularization, it may possible to anticipate whether an ischemic ulcer will heal or not.

A Pilot Study Investigating the Use of Regional Oxygen Saturation as a Predictor of Ischemic Wound Healing Outcome after Endovascular Treatment in Patients with Chronic Limb-Threatening Ischemia.

Objective: To determine the prognostic value of regional tissue oxygenation saturation (rSO2) for ulcer healing after endovascular treatment (EVT) of peripheral arterial disease (PAD). Materials and Methods: Among PAD patients, 34 patients with chronic limb-threatening ischemia underwent EVT for limb salvage. We retrospectively analyzed the cutoff rSO2 values on postoperative day 1 to predict ulcer healing and patient prognosis. Skin perfusion pressure (SPP) and transcutaneous oxygen pressure (TcPO2) were also used to assess wound healing. Results: A finger-mounted tissue oximeter can easily measure rSO2 on the dorsal foot. Among the 34 patients, the ulcer healed in 25, and no changes were observed in 2 patients at 1 month after EVT. However, 7 patients needed major amputation at the same time. Wound healing was achieved in all patients with rSO2≥50%. With this cutoff, the sensitivity and specificity of the new device for wound healing were 100% and 64%, respectively. In all the wound healing cases, SPP was ≥45 mmHg, and TcPO2 was ≥40 mmHg. Conclusion: To assess limb ischemia, rSO2 can be measured quickly and easily using this device. We suggest that an rSO2>50% shows good prognosis for ulcer healing.

Potential role of transforming growth factor-beta 1/Smad signaling in secondary lymphedema after cancer surgery.

Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and skin fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor-beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting fibrosis. Suppression of myofibroblast-dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting skin fibrosis in human secondary lymphedema after cancer surgery.

K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease, which frequently results in fatal rupture; however, no pharmacologic treatment exists to inhibit AAA growth and prevent rupture. In this study, we investigated whether K-134, a novel phosphodiesterase 3 inhibitor, could limit the progression and rupture of AAA using multiple experimental models. METHODS: A hypoperfusion-induced AAA rat model was developed by inserting of a small catheter and via tight ligation of the infrarenal aorta. Rats were fed with a 0.15% K-134-containing diet (K-134(+) group) or a normal diet (K-134(-) group) from 7 days before the experiment to 28 days after model creation (pretreatment protocol). After the administration period, elastin fragmentation, macrophage infiltration, reactive oxygen species expression, matrix metalloproteinase levels, aneurysmal tissue hypoxia, and adventitial vasa vasorum (VV) stenosis were assessed. In the delayed treatment protocol, rats with AAA >3 mm were randomly divided to K-134(+) or K-134(-) group 7 days after model creation, and the effect of K-134 on suppressing preexisting AAA was examined. Further, elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model were also used to examine the ability of K-134 to prevent rupture. RESULTS: K-134 prevented AAA rupture and significantly improved survival in the pretreatment protocol (P < .01). In the K-134(+) group, elastin degeneration was prevented; macrophage infiltration and reactive oxygen species production were significantly decreased. At 14 days, the enzymatic activity of matrix metalloproteinase-9 was significantly decreased. Further, K-134 inhibited intimal hyperplasia and VV stenosis. Expressions of hypoxic markers, hypoxia-inducible factor-1α, and pimonidazole, in the aneurysmal wall were also attenuated. In the delayed treatment protocol, K-134 also improved survival of rats with preexisting AAA. Similarly, in the elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model, K-134 inhibited rupture and significantly improved survival (P < .01). CONCLUSIONS: K-134 prevented the rupture of AAA and improved survival through suppressing inflammatory reaction. The inhibition of intimal hyperplasia in the adventitial VV may be associated with reduced hypoxia in the aneurysmal tissue. (JVS-Vascular Science 2020;1:219-32.). CLINICAL RELEVANCE: This study shows that K-134, a novel phosphodiesterase 3 inhibitor, suppressed abdominal aortic aneurysm (AAA) rupture. Considering that K-134 had already undergone a phase Ⅱ study in the United States for claudication in peripheral artery occlusive disease patients with good tolerance, K-134 may become a promising new therapeutic option for AAAs and could undergo clinical trials for patients with small AAA.

Development of a Noninvasive Skin Evaluation Method for Lower Limb Lymphedema.

Background: The skin's condition is altered in lymphedema patients, and evaluating this change is important. Some noninvasive methods for evaluating skin condition have been reported, especially in upper limb lymphedema. However, evaluating the skin in lower limb lymphedema remains challenging and is often limited to palpation. We aimed to develop a noninvasive skin evaluation method for lower limb lymphedema patients. Methods and Results: Twenty-five lower limb lymphedema patients were included. Skin induration and elasticity were measured using Indentometer® IDM 400 and Cutometer® MPA580. The relationship between the properties of skin from the healthy forearm and thigh, those of the affected thigh, and age was analyzed. Predicted skin induration age (IA) and elasticity age (EA) were calculated from the forearm, whereas actual values were calculated from the thigh, and the differences (ΔIA and ΔEA) were assessed. Patients were classified according to the International Society of Lymphology clinical staging system, and the differences in ΔIA and ΔEA were analyzed among the three groups (healthy, stage I/IIa, and stage IIb/III). Skin biopsy was performed in five unilateral lower limb lymphedema patients, and the dermal elastic fiber area was determined using microscopy with Elastica van Gieson staining. ΔEA significantly increased with disease progression, but ΔIA did not change significantly. Microscopy revealed elastic fiber filamentous changes, with decreased elastic fiber areas in lymphedema-affected skin. Conclusion: To our knowledge, this is the first report to evaluate lower limb skin elasticity in lymphedema quantitatively and noninvasively. ΔEA is useful for evaluating skin condition progression in lymphedema patients.

The Role of Animal Models in Elucidating the Etiology and Pathology of Abdominal Aortic Aneurysms: Development of a Novel Rupture Mechanism Model.

Existing animal models do not replicate all aspects of abdominal aortic aneurysms (AAAs), including the rupture mechanisms. From histopathological analyses conducted in humans, it has been found that the vasa vasorum of the AAA wall is the starting point of circulatory failure and that bulging and dilatation of the abdominal aorta occurs through inflammation and tissue degeneration. We created a new animal model (the hypoperfusion-induced model) of AAAs. In this study, we describe the current animal models of AAAs and present the utility of our new model of AAAs.

Utility of a Finger-Mounted Tissue Oximeter with Near-Infrared Spectroscopy to Evaluate Limb Ischemia in Patients with Peripheral Arterial Disease.

Objective: To investigate whether a finger-mounted tissue oximeter is useful in evaluating limb blood flow in patients with peripheral arterial disease (PAD). Materials and Methods: Seventy-two patients with PAD were included, and the ankle-brachial index (ABI), transcutaneous oxygen pressure (TcPO2), and skin perfusion pressure (SPP) were measured. The regional tissue oxygenation saturation (rSO2) was measured using a finger-mounted tissue oximeter at the ankle, dorsal foot, and each dorsal and plantar toe. Correlations between rSO2 and ABI and between TcPO2 and SPP were analyzed. The patients were divided into three groups: Fontaine IIa (F-IIa), IIb (F-IIb), and III and IV (F-III/IV) groups. The difference in rSO2 between each group was analyzed. Results: Significant correlations were observed between rSO2 and TcPO2 and between rSO2 and SPP. TcPO2 and SPP in the F-III/IV group were significantly lower than those in the F-IIa group. rSO2 in the F-IIb and F-III/IV groups was significantly lower than that in the F-IIa group. Conclusion: The measurement of rSO2 using finger-mounted tissue oximetry is quick, simple, and painless. It can be used on any skin area and is useful to evaluate limb circulation in patients with PAD.

Characteristics of Symptomatic Pulmonary Thromboembolism among Postoperative and Hospitalized Patients.

Backgrounds: Pulmonary thromboembolism (PTE) is severe complication which may arise during all medical service. The purpose of this study is to evaluate inpatient symptomatic PTE. Materials and Methods: From 2005 to 2016, we experienced 75 symptomatic PTE patients among 600 venous thromboembolism patients. According to the place of occurrence, patients were divided to inpatient group and outpatient group. We further divided inpatient group to surgical group and non-surgical group. Results: Inpatients group, 38 had PTE (surgical: 23, non-surgical: 15). Outpatients group, 37 had PTE (with medical practice: 22, without medical practice: 15). Severity of PTE were follows; cardiac arrest 2, massive 13, sub-massive 18, non-massive 42. In surgical group, anticoagulation had been used in 3/23 (13.6%), intermittent pneumatic compression had been used in 16/23 (72.9%), compression stockings had been used in 20/23 (90.9%). In non-surgical group, no anticoagulation had not been used, intermittent pneumatic compression had been used in 2/15 (13.3%), compression stockings had been used in 2/15 (13.3%). Conclusion: As PTE prophylaxis, anticoagulation had been scarcely used in surgical group. Delayed anticoagulation may decrease symptomatic PTE in surgical patients. Despite adequate prophylaxis, PTE cannot be prevented completely. Medical staff and patients should recognize the risk of PTE together. (This is a translation of Jpn J Phlebol 2018; 29(1): 33-40.).

Axillo-Axillary Artery Bypass With Coil Embolization of the Innominate Artery for a Traumatic Innominate Artery Aneurysm: A Case Report.

BACKGROUND: Innominate artery aneurysm (IAA) is a rare cervical artery aneurysm. Although atherosclerosis is its most common cause, IAAs due to cervical injury are often reported. Operative indications for IAAs include rupture or symptomatic aneurysm, saccular aneurysm, aneurysm with a diameter of 3 cm or greater, and aneurysmal change of the origin of the innominate artery. Although the ligature of the innominate artery or open surgical repair is well described, the usefulness of endovascular repair has also recently been reported. Herein, we report a case of traumatic IAA with infection in the cervical region after tracheostomy. CASE PRESENTATION: A 40-year-old man with cholecystolithiasis planned to undergo laparoscopic cholecystectomy at another hospital. Urgent tracheostomy was performed because of laryngeal edema at the induction of general anesthesia. Enhanced computed tomography angiography 1 week after the tracheostomy revealed a saccular IAA. The patient was deemed to be at high risk for aneurysm rupture and was referred to our hospital. Preoperative Matas test, Allcock test, and innominate arterial stump pressure measurement were performed to assess the cerebral blood flow and ischemic tolerance of the brain. These examinations showed the patency of the circle of Willis. An axillo-axillary artery bypass with coil embolization of the innominate artery was performed to avoid postoperative vascular graft infection. No postoperative complications such as infection or cerebral infarction occurred. Magnetic resonance imaging angiography performed 6 months after surgical treatment showed that the aneurysm had disappeared, and patency of the bypass graft was present. There were no postoperative complications, such as neurological deficits or graft infection, at more than 5 years after surgery. CONCLUSIONS: We report a successfully treated case of IAA after tracheostomy. Axillo-axillary artery bypass with coil embolization of the innominate artery is an effective treatment of IAA with cervical infection.

Hypoperfusion of the Aortic Wall Secondary to Degeneration of Adventitial Vasa Vasorum Causes Abdominal Aortic Aneurysms.

BACKGROUND: An abdominal aortic aneurysm (AAA), which affects approximately 10% of Japanese men aged ≥ 65 years, is frequently associated with hypertension, dyslipidemia, and other lifestyle- related diseases. The development of an AAA is attributed to chronic inflammation concomitant with arteriosclerotic changes. However, an accurate pathomechanism associated with AAA remains uncertain, and questions such as why only a particular group/percentage of patients with arteriosclerosis develop aneurysms and how diabetes suppresses aneurysm development remain unanswered. OBJECTIVE: We examined a novel mechanism to develop AAA based on histopathological findings following analysis of the human AAA tissues. Additionally, based on these findings, we developed a new animal model of AAA, in which the histopathological characteristics are similar to human AAA tissue. RESULTS: Recently, we identified stenosis of the vasa vasorum (VV) in aortic segments showing dilatation. The aorta is the largest artery in our circulatory system. Under physiological conditions, the inner layer of the aorta is nourished via direct diffusion of nutrients from the luminal blood flow, whereas the outer adventitia is primarily perfused by the VV. Therefore, hypoperfusion of the VV induces hypoxia and subsequent inflammation and tissue degeneration of the aortic wall, resulting in aneurysm formation. Based on these findings, we established an AAA animal model by reducing the blood flow through the VV to the aortic wall. AAA was successfully reproduced in our animal model. Histopathological findings in this model were indistinguishable from those observed in humans, and pronounced abnormality in lipid composition in blood vessel adventitia was also observed. CONCLUSION: Thus, hypoperfusion of the aortic wall appeared to be sufficient to cause inflammationinduced AAA. These findings may provide potential targets for novel therapeutics for the management of an AAA.

Creation of a Rodent Model of Abdominal Aortic Aneurysm by Blocking Adventitial Vasa Vasorum Perfusion.

The adventitial vasa vasorum (VV) provides oxygen and nourishment to the aortic wall. Hypoxia in the aortic wall can cause enlarged abdominal aortic aneurysms (AAAs). This article introduces and describes a standard protocol used to induce AAAs through adventitial VV hypoperfusion created with a combination of polyurethane catheter insertion into the aortic lumen and suture ligation of the infrarenal abdominal aorta. The protocol involves the use of male rats weighing 300-400 g, which are provided food and water ad libitum. After laparotomy with a ventral midline abdominal incision, exfoliation of the aorta is performed, which blocks blood flow from the perivascular tissue. Aortotomy involving a small incision adjacent to the renal artery branches is performed, and a polyurethane catheter is inserted using an 18-gauge indwelling needle. After repairing the incision, tight ligation of the aorta over the catheter blocks VV blood flow from the proximal direction through the aortic wall without disturbing the aortic blood flow. This technique can induce an AAA with progressive aortic dilatation. The greatest benefit of this model is that VV hypoperfusion causes tissue hypoxia and the development of an infrarenal AAA, which has morphological and pathological characteristics similar to those of a human AAA.

Lysophosphatidylcholine Acyltransferase-3 Expression Is Associated with Atherosclerosis Progression.

Free arachidonic acid (AA) is an important precursor of lipid mediators such as leukotrienes and prostaglandins that induces inflammation and is associated with atherosclerosis progression. Recent studies have shown that lysophosphatidylcholine acyltransferase-3 (LPCAT3) converts lysophosphatidylcholine (LPC) and free AA into phosphatidylcholine (PC)-containing AA (arachidonyl-PC) and thereby can regulate intracellular free-AA levels. However, the association between LPCAT3 and atherosclerosis remains to be established. In this study, we analyzed human and mouse atherosclerotic tissues to gain insight into the arachidonyl-PC metabolism involving LPCAT3 using imaging mass spectrometry. The data revealed a complementary distribution of arachidonyl-PC and LPC in human atherosclerotic tissues with arachidonyl-PC decreasing and LPC increasing as atherosclerosis progressed. Furthermore, we found a homologous distribution of LPCAT3 expression and arachidonyl-PC based on atherosclerotic progression. In contrast, in ApoE-deficient mice, atherosclerosis increased both arachidonyl-PC accumulation and LPCAT3 expression. Taken together, these findings suggest that the regulation of LPCAT3 expression might be associated with atherosclerotic progression in humans.

Adipocyte in vascular wall can induce the rupture of abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a vascular disease involving the gradual dilation of the abdominal aorta. It has been reported that development of AAA is associated with inflammation of the vascular wall; however, the mechanism of AAA rupture is not fully understood. In this study, we investigated the mechanism underlying AAA rupture using a hypoperfusion-induced animal model. We found that the administration of triolein increased the AAA rupture rate in the animal model and that the number of adipocytes was increased in ruptured vascular walls compared to non-ruptured walls. In the ruptured group, macrophage infiltration and the protein levels of matrix metalloproteinases 2 and 9 were increased in the areas around adipocytes, while collagen-positive areas were decreased in the areas with adipocytes compared to those without adipocytes. The administration of fish oil, which suppresses adipocyte hypertrophy, decreased the number and size of adipocytes, as well as decreased the risk of AAA rupture ratio by 0.23 compared to the triolein administered group. In human AAA samples, the amount of triglyceride in the adventitia was correlated with the diameter of the AAA. These results suggest that AAA rupture is related to the abnormal appearance of adipocytes in the vascular wall.