Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　- A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study).

BACKGROUND: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5-2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer. CONCLUSIONS: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

Lower limb ischemia due to popliteal artery compression by Baker cyst.

A Baker cyst is the most common mass around the knee joint. It is mostly asymptomatic; however, it may cause knee pain or focal swelling because of compression of vein or nerve. Herein, we report a case of Baker cyst obstructing arterial flow and causing intermittent claudication. An attached polycystic mass was found posterior to the popliteal artery. Needle aspiration was ineffective, and the patient experienced recurrent lower leg pain. Surgical resection was performed, and the patient became symptom free. Baker cyst may cause lower limb ischemia through obstruction of arterial flow, requiring surgical intervention.

Daily transient discontinuation of extracorporeal LVAD to prevent thromboembolism of mechanical aortic valve prosthesis.

Patients with mechanical aortic valves are generally contraindicated for left ventricular assist device (LVAD) insertion because the prosthetic valve often becomes fixed in closed position. A 41-year-old woman with mechanical aortic valve prosthesis experienced sudden chest pain and developed cardiogenic shock. A paracorporeal pulsatile LVAD and a monopivot centrifugal pump as a right VAD (RVAD) were implanted. The mechanical aortic valve was intentionally left in place. Soon after the operation, LVAD support was discontinued daily for few seconds to allow the mechanical aortic valve to open and to avoid thrombus formation. The patient was successfully weaned off RVAD and received anticoagulation therapy with warfarin. On postoperative day 141, she was transferred to a university hospital where a HeartMate II LVAD was implanted, and the aortic valve was successfully replaced with a bioprosthetic valve. The patient is currently awaiting heart transplantation.

Clinical features and predictors of patients with critical limb ischemia who responded to autologous mononuclear cell transplantation for therapeutic angiogenesis.

The clinical features of patients with critical limb ischemia (CLI) who responded to angiogenesis using autologous peripheral blood mononuclear cell transplantation (PB-MNC) have not yet been fully characterized, and there are no useful predictors to judge the curative effect in the early period after PB-MNC. This study sought to clarify the clinical features and predictors in patients with CLI who were successfully treated using PB-MNC. 30 consecutive patients [arteriosclerosis obliterans: 24 patients, thromboangiitis obliterans: 6 patients] who were diagnosed with major amputation despite maximal medical therapy were enrolled in this study. The study endpoint was major amputation within 3 months after PB-MNC. The collected data were evaluated for correlation between patients with and without major amputation within 3 months after PB-MNC. Six patients underwent major amputation and 1 patient underwent minor amputation. In the patients with major amputation, transcutaneous oxygen tension before PB-MNC and transplanted CD34-positive cells were lower than those of patients without major amputation. In the patients with amputation, interleukin-6 (IL-6) continued to increase after the first PB-MNC, and basic fibroblast growth factor (bFGF) decreased within 3 days after the first PB-MNC. PB-MNC was useful for the patients who were managed for inflammation and who had revascularization of the upper-popliteal arteries and two of the infra-popliteal arteries by endovascular and/or surgical revascularization. Variation in IL-6 and bFGF in the early period after PB-MNC could be useful predictors for the requirement of amputation within 3 months after PB-MNC.

Factors associated with a low initial cerebral oxygen saturation value in patients undergoing cardiac surgery.

Regional cerebral oximetry using near-infrared spectroscopy device, an INVOS 5100 C (Medtronic, Minneapolis, MN, USA), during cardiac surgery aims to avoid perioperative neurological impairment, especially during cardiopulmonary bypass. However, it is not uncommon to encounter critically low initial cerebral regional oxygen saturation or a low value unresponsive to intervention. Therefore, it is important to identify factors associated with low saturation value other than true cerebral hypoxia. We investigated the relationship between preoperative regional cerebral oxygen saturation and clinical variables during cardiac surgery. From January 2013 to May 2016, 462 patients underwent elective cardiac surgery. Patient's ≤12 years of age, with acute cerebral infarction, with previous intracranial hemorrhage or neurosurgery, with concomitant aortic surgery, and having off-pump coronary artery bypass surgery were excluded. The remaining 223 patients were monitored by intraoperative regional cerebral oximetry. Univariate analysis found that scalp-cortex distance, cerebrospinal fluid thickness, left ventricular ejection fraction, hemoglobin concentration, estimated glomerular filtration rate, and hemodialysis were significantly correlated with the initial regional oxygen saturation value. Multiple regression analysis revealed that scalp-cortex distance, left ventricular ejection fraction, hemoglobin, and hemodialysis remained as significant variables. A receiver operating characteristic analysis found that for a low initial regional oxygen saturation value of 40%, the thresholds of scalp-cortex distance, left ventricular ejection fraction, and hemoglobin concentration were 17.6 mm, 45.2%, and 7.5 g/dl, respectively. In conclusion, brain atrophy, poor left ventricular function, anemia, and hemodialysis were associated with low initial cerebral regional oxygen saturation values in adult cardiac surgery patients.

Retroperitoneal schwannoma between the inferior vena cava and the abdominal aorta resected by laparoscopic surgery: A case report.

A 22-year-old woman presented with backache. Imaging analysis revealed a retroperitoneal tumor, 40 mm in diameter, surrounded by the abdominal aorta, inferior vena cava, caudate lobe of liver, and the left renal vein. The tumor consisted of multilocular cystic parts, and a solid part showed contrast enhancement. The possibility of malignancy could not be excluded, so we planned a laparoscopic tumorectomy. After placement of a transjugular vascular sheath for an occlusion balloon catheter in the inferior vena cava, the operation was performed with six ports. There was a strong fibrotic adhesion between the tumor and the abdominal aorta, with other weak adhesions. The tumor was successfully resected by a laparoscopic operation with minimal bleeding. The histopathological diagnosis was a benign schwannoma. This case demonstrates that a retroperitoneal tumor adjacent to major vessels can be resected safely by laparoscopic surgery if the surgeon is especially careful of the possibility of accidental bleeding.

VEGFR1-positive macrophages facilitate liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion injury.

Liver repair after acute liver injury is characterized by hepatocyte proliferation, removal of necrotic tissue, and restoration of hepatocellular and hepatic microvascular architecture. Macrophage recruitment is essential for liver tissue repair and recovery from injury; however, the underlying mechanisms are unclear. Signaling through vascular endothelial growth factor receptor 1 (VEGFR1) is suggested to play a role in macrophage migration and angiogenesis. The aim of the present study was to examine the role of VEGFR1 in liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion (I/R). VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK-/- mice) and wild-type (WT) mice were subjected to hepatic warm I/R, and the processes of liver repair and sinusoidal reconstruction were examined. Compared with WT mice, VEGFR1 TK-/- mice exhibited delayed liver repair after hepatic I/R. VEGFR1-expressing macrophages recruited to the injured liver showed reduced expression of epidermal growth factor (EGF). VEGFR1 TK-/- mice also showed evidence of sustained sinusoidal functional and structural damage, and reduced expression of pro-angiogenic factors. Treatment of VEGFR1 TK-/- mice with EGF attenuated hepatoceullar and sinusoidal injury during hepatic I/R. VEGFR1 TK-/- bone marrow (BM) chimeric mice showed impaired liver repair and sinusoidal reconstruction, and reduced recruitment of VEGFR1-expressing macrophages to the injured liver. VEGFR1-macrophages recruited to the liver during hepatic I/R contribute to liver repair and sinusoidal reconstruction. VEGFR1 activation is a potential therapeutic strategy for promoting liver repair and sinusoidal restoration after acute liver injury.

Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment.

Recruited macrophages play a critical role in liver repair after acute liver injury. Leukotriene B4 (LTB4) is a potent chemoattractant for macrophages. In this study, we investigated the role of LTB4 receptor type 1 (BLT1) in liver repair during hepatic ischemia/reperfusion (I/R) injury. BLT1-knockout mice (BLT1(-/-)) or their wild-type counterparts (WT) were subjected to partial hepatic I/R. Compared with WT, BLT1(-/-) exhibited delayed liver repair and hepatocyte proliferation accompanied by a 70% reduction in the recruitment of macrophages and a 70-80% attenuation in hepatic expression of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Disruption of BLT1 signaling also reduced the expression of EGF by 67% on recruited macrophages expressing VEGFR1 in the injured liver. Treatment of WT mice with an EGF-neutralizing antibody delayed liver repair and reduced macrophage recruitment, compared with control immunoglobulin G (IgG). BLT1 signaling enhanced the expression of VEGF, VEGFR1, and EGF in isolated peritoneal macrophages in vitro. These results indicate that BLT1 signaling plays a role in liver repair after hepatic I/R through enhanced expression of EGF in recruited macrophages and that the development of a specific agonist for BLT1 could be useful for liver recovery from acute liver injury.

Calcitonin gene-related peptide facilitates revascularization during hindlimb ischemia in mice.

It is known that the neural system plays a fundamental role in neovascularization. A neuropeptide, calcitonin gene-related peptide (CGRP), is widely distributed in the central and peripheral neuronal systems. However, it remains to be elucidated the role of CGRP in angiogenesis during ischemia. The present study examined whether endogenous CGRP released from neuronal systems facilitates revascularization in response to ischemia using CGRP knockout mice (CGRP-/-). CGRP-/- or their wild-type littermates (CGRP+/+) were subjected to unilateral hindlimb ischemia. CGRP-/- exhibited impaired blood flow recovery from ischemia and decreased capillary density expressed in terms of the number of CD-31-positive cells in the ischemic tissues compared with CGRP+/+. In vivo microscopic studies showed that the functional capillary density in CGRP-/- was reduced. Hindlimb ischemia increased the expression of pro-CGRP mRNA and of CGRP protein in the lumbar dorsal root ganglia. Lack of CGRP decreased mRNA expression of growth factors, including CD31, vascular endothelial growth factor-A, basic fibroblast growth factor, and transforming growth factor-ß, in the ischemic limb tissue. The application of CGRP enhanced the mRNA expression of CD31 and VEGF-A in human umbilical vein endothelial cells (HUVECs) and fibroblasts. Subcutaneous infusion of CGRP8-37, a CGRP antagonist, using miniosmotic pumps delayed angiogenesis and reduced the expression of proangiogenic growth factors during hindlimb ischemia. These results indicate that endogenous CGRP facilitates angiogenesis in response to ischemia. Targeting CGRP may provide a promising approach for controlling angiogenesis related to pathophysiological conditions.

Impact of preoperative and postoperative atrial fibrillation on outcome after mitral valvuloplasty for nonischemic mitral regurgitation.

OBJECTIVE: We sought to determine the impact of preoperative or postoperative atrial fibrillation on survival, stroke, and cardiac function after mitral valvuloplasty for mitral regurgitation. METHODS: Between 1991 and 2003, 1026 patients with nonischemic/noncardiomyopathy mitral valve regurgitation underwent mitral valve plasty in 3 centers; 663 patients remained in sinus rhythm (group A), and 363 patients had atrial fibrillation or flutter preoperatively (group B) with concomitant maze procedures (group BM, n = 163) or without maze procedures (group BN, n = 200). RESULTS: Eight-year freedom from cardiovascular-related death was better in group A (99.3%) than group B (BM: 96.9%, BN: 81.6%) ( P < .001) and also better in group BM than group BN ( P = .007). The adjusted hazard ratio of group B versus group A for preoperative differences was 5.1 (95% confidence interval: 1.8-14.8). Eight-year freedom from stroke was better in group A (99.2%) than group B (BM: 98.2%, BN: 82.6%) ( P < .001) and also better in group BM than group BN ( P < .001). Patients with preoperative atrial fibrillation had larger left atria and left ventricular systolic dimensions. The adjunct maze procedure improved left ventricular systolic dimensions over mitral repair alone (group A vs B: P = .359; group BM vs BN: P = .001). CONCLUSION: Preoperative permanent/persistent atrial fibrillation was associated with a dilated left atrium and reduced left ventricular function in patients with mitral regurgitation. Including the maze procedure with mitral repair improved survival, late cardiac function, and freedom from late stroke.

[Quantitative evaluation of deformity of the iliac artery during extension and flexion of the hip joint: three-dimensional evaluation using MDCT].

We performed CT-angiography twice, first hip joint extension, followed by second flexion. Using vessel analysis software, we placed several points of interest at equal intervals on the center line of the iliac artery, from the bifurcation to the femoral artery inguinal portion, and recorded the their three-dimensional coordinates. We also marked the circumference, which passes by three points that add the respective next point and prior point to each reference point. This curvature (the inverse number of the radius) was utilized as the index that displays crookedness. This method was able to estimate quantitatively the grade of crookedness, and, by comparing an equidistant point from the bifurcation, to show the changes in grade at flexion of the hip joint.

Early and late stroke after mitral valve replacement with a mechanical prosthesis: risk factor analysis of a 24-year experience.

OBJECTIVE: We evaluated risk factors for mortality and stroke after mechanical mitral valve replacement between May 1977 and December 2001. METHODS: Early and late mortality and stroke were assessed. Potential predictors of mortality and stroke were entered into a Cox proportional hazards model. Actuarial survival and freedom from stroke were determined by a log-rank test. RESULTS: Mitral valve replacement was performed in 812 patients. Concomitant procedures included left atrial appendage closure in 493 (61%) patients, tricuspid annuloplasty-replacement in 348 (43%) patients, maze procedure in 185 (23%) patients, plication of the left atrium in 148 (18%) patients, and other procedures in 151 (19%) patients. Five-year actuarial survival was 91.1% +/- 2.3%. Freedom from stroke at 8 years was significantly better in patients with sinus rhythm versus atrial fibrillation (P <.001). Ninety-nine percent of patients with mitral valve replacement combined with a maze procedure were free from stroke, whereas only 89% of patients with mitral valve replacement alone were free from stroke at 8 years after surgical intervention. Seventy-two patients had late stroke; sixty-five patients (90%) were in atrial fibrillation, and 47 (65%) patients had the left atrial appendage closed. Multivariate analysis showed that late atrial fibrillation (odds ratio, 3.39; 95% confidence interval, 1.72-6.67; P =.0001) and omission of the maze procedure (odds ratio, 3.40; 95% confidence interval, 1.14-10.14; P =.003) were the significant risk factors for late stroke. CONCLUSIONS: Persistent atrial fibrillation was the most significant risk factor for late stroke after mechanical mitral valve replacement. Restoration of sinus rhythm with a maze procedure nearly eliminated the risk of late stroke, whereas neither closure of the left atrial appendage nor therapeutic anticoagulation prevented this complication.

Impact of Cox maze procedure on outcome in patients with atrial fibrillation and mitral valve disease.

OBJECTIVE: We sought to determine whether the Cox maze procedure provides additional benefit to patients with atrial fibrillation undergoing mitral valve operations. METHODS: Between May 1992 and August 2000, we performed 258 Cox maze procedures with mitral valve replacement (n = 147) or mitral valve repair (n = 111). We compared the outcomes of these patients with those of 61 control patients with preoperative atrial fibrillation who underwent mitral valve replacement alone during the same interval. The three cohorts were similar in age, sex, and proportion of patients in preoperative New York Heart Association functional class 3 or 4. RESULTS: Although 5-year survivals were similar among the groups (94% for mitral valve replacement alone, 95% for mitral valve replacement plus maze, and 97% for mitral valve repair plus maze), freedoms from atrial fibrillation at 5 years were significantly higher in the mitral valve replacement plus maze group (78%) and the mitral valve repair plus maze group (81%) than in the mitral valve replacement group (6%, P <.0001). Freedoms from stroke at 5 years were 97% for the mitral valve replacement plus maze group, 97% for the mitral valve repair plus maze group, and only 79% for mitral valve replacement group (P <.0001). Multivariable analysis with Cox hazard model revealed that the most significant risk factor for late stroke was the omission of the Cox maze procedure (P =.003). CONCLUSIONS: The addition of the Cox maze procedure to mitral valve repair and replacement was safe and effective for selected patients. Elimination of atrial fibrillation significantly decreased the incidence of late stroke.

Blockade of bradykinin B(2) receptor suppresses acute pancreatitis induced by obstruction of the pancreaticobiliary duct in rats.

1. The involvement of bradykinin (BK) B(2) receptor in acute pancreatitis induced by pancreaticobiliary duct ligation was investigated in rats. 2. The activities of amylase and lipase in the serum, the water content of the pancreas, and vacuolization of the acinar cells were significantly increased 2 h after obstruction of the duct in Sprague-Dawley rats. 3. Elevated serum amylase activity, increased pancreatic oedema, and damage of the pancreatic tissue were significantly less marked in plasma kininogen-deficient, B/N-Katholiek rats than in the normal strain, B/N-Kitasato rats 2 h after the ligation. 4. Obstruction of the pancreaticobiliary duct augmented the level of (1-5)-BK (Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)), a stable BK metabolite, in the blood from 73.0+/-21.7 pg ml(-1) at 0 h to 149.8+/-38.0 pg ml(-1) at 2 h after the induction of pancreatitis in SD rats. 5. Administration of a BK B(2) receptor antagonist, FR173657 (100 mg kg(-1), p.o.) or Hoe140 (100 nmol kg(-1), s.c.), reduced the elevation of amylase and lipase activities in the serum and of pancreatic water content in a dose-dependent manner. The effective attenuation of oedema formation and vacuolization by the antagonists was also confirmed light-microscopically. In contrast, treatment with gabexate mesilate or indomethacin did not cause significant suppression of the pancreatitis. 6. These findings suggest a possible involvement of kinin B(2) receptor in the present pancreatitis model. Furthermore, they point to the potential usefulness of the B(2) receptor in clinical acute pancreatitis.