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OBJECTIVE: Massive pulmonary embolism is relatively rare but a potentially life-threatening condition. The purpose of this study was to analyse the outcome of pulmonary embolectomy in registered data from the Japanese Society of Pulmonary Embolism Research (JaSPER). METHODS: From 1994 to 2006, 1661 cases of acute pulmonary embolism were registered in the JaSPER database. Retrospective analysis of 32 patients undergoing pulmonary embolectomy was conducted. The overall incidence of pulmonary embolectomy was 1.9% [95% confidence interval (CI): 1.8-3.2%]. The mean age of patients was 57 years and 66% were female. RESULTS: Overall mortality of pulmonary embolectomy was 18.8% [95% CI: 5.2-25.6%]. Most of the patients had massive or submassive pulmonary thromboembolism, and three patients experienced cardiopulmonary arrest before embolectomy. Ten patients received preoperative percutaneous cardiopulmonary bypass, and mortality was 30% in this subgroup. CONCLUSIONS: Pulmonary embolectomy is an effective therapeutic option for patients with massive or submassive pulmonary embolism. Prompt triage of patients with haemodynamic instability is important.

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BACKGROUND: The Japanese Society of Anesthesiologists (JSA) has maintained records of the annual incidence and characteristics of perioperative pulmonary thromboembolism (perioperative PTE) since 2002. The aim of this paper was to provide recent results of the JSA annual study conducted in 2008, and to determine the current factors that tend to prevent perioperative venous thromboembolism (VTE) in Japan. METHODS: A comprehensive questionnaire designed by the JSA PTE working group was mailed to all institutions certified as teaching hospitals by JSA. The data tics of patients with perioperative PTE, such as types of diseases and surgeries, age, sex, methods used for the prevention of VTE (in some cases), and prognosis of perioperative PTE. RESULTS: The rate of effective responses was 56.1% (634/1116), and 1,177,626 surgeries were registered during the study period. There were 324 patients who were reported to have had PTE, and the incidence was 2.75 per 10,000 surgeries. The incidence of perioperative PTE in 2008 did not change significantly from that in 2005-07. The surgeries that most commonly resulted in perioperative PTE were limb and/or hip joint surgery (5.71 per 10,000 surgeries), craniotomy (4.64 per 10,000), and thoracotomy with laparotomy (3.46 per 10,000 surgeries). The mortality rate of perioperative PTE in 2008 was found to have significantly decreased from that in 2005-07 (15.6% vs. 22.4%; P = 0.01). Further, the rate of patients who received anticoagulant drugs in 2008 was significantly higher than that in 2005-07 (17.6% vs. 10.8%; P = 0.0018). Individual guidelines for the prevention of perioperative VTE were adopted in 55.4% of the training institutions. CONCLUSIONS: The increase in the percentage of patients who received anticoagulant drugs around the time of the operation, and the decreased mortality of patients with perioperative PTE suggested that the prophylaxis for perioperative VTE with anticoagulant drugs reduces perioperative mortality.

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OBJECTIVE: In Japan, there have been no reports on the time-trends of mortality rates from pulmonary heart disease without pulmonary embolism (PHD). Our aim was to examine the annual changes of mortality in Japan. MATERIALS AND METHODS: Annual age-adjusted and age-specific PHD mortality for Japanese residents during 1979-2006 were calculated from "Vital statistics of Japan" and census data and population estimates for intercensal years. RESULTS: The number of age-adjusted deaths from PHD continued to decrease throughout the study period. The age-specific mortality from PHD increased throughout the life span except below 1 year old and decreased in recent years. Male mortality was greater at most ages. In Poisson regression analysis, the relative risk of death from PHD was increased in males and the aged except below 1 year-age, and decreased in recent years. The annual number of deaths from idiopathic pulmonary arterial hypertension/heritable pulmonary arterial hypertension (IPAH/HPAH) continued to increase throughout the study period. The number of annual new cases with IPAH/HPAH was estimated to be about 400 in a recent period of 10 years. CONCLUSION: The annual number of deaths from PHD decreased, and those from IPAH/HPAH increased significantly during 1979-2006 in Japan.

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Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by pulmonary hypertension caused by thromboembolism of the pulmonary artery. Etiology of CTEPH may be heterogeneous and is largely unknown, but genetic factors are considered to be involved in the etiology. It has been reported that deep vein thrombosis (DVT) and/or coagulation factor variants are predisposing factors to CTEPH. However, more than half of the CTEPH patients, especially the Japanese, do not have prior DVT or coagulation abnormality, suggesting that there should be other risk factors for CTEPH. Moreover, there are several reports on the association between CTEPH and human leukocyte antigen (HLA). To further clarify the HLA-linked gene(s) controlling the susceptibility to CTEPH, 160 patients (99 without DVT and 61 with DVT) and 380 healthy controls were analyzed for polymorphisms in 15 microsatellite markers and 5 genes in the HLA region. We found a strong association of HLA markers with the DVT-negative CTEPH, DPB1(*)0202 (odds ratio (OR)=5.07, 95% confidence interval (CI)=2.52-10.19, P=0.00000075, corrected P-value (Pc)=0.00014), IKBL-p(*)03 (OR=2.33, 95% CI=1.49-3.66, P=0.00017, Pc=0.033) and B(*)5201 (OR=2.47, 95% CI=1.56-3.90, P=0.000086, Pc=0.016), whereas no significant association was observed for the DVT-positive CTEPH. The comparison of clinical characteristics of patients stratified by the presence of susceptibility genes implied that the DPB1 gene controlled the severity of the vascular lesion, whereas the IKBL gene (NFKBIL1) was associated with a relatively mild phenotype.

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BACKGROUND: Sequential changes in the hemodynamic effect of chronic epoprostenol therapy raise the following questions. Does an increase in cardiac output (CO) precede lowering of the pulmonary artery pressure (PAP) over the time course of improvement? What are the characteristics of good responders to chronic epoprostenol treatment? METHODS AND RESULTS: Hemodynamics were evaluated by catheter examination. Most patients still alive after >1 year showed an increase in CO either with no change in mean PAP or accompanied by a decrease in mean PAP during increased dosing of epoprostenol. Immediately before cessation of the increase in epoprostenol dose in good responders, the ratio of total pulmonary resistance to total systemic resistance was low, and the pulmonary artery wedge pressure minus right atrial pressure was high compared with the newest data in poor responders. One year after fixing at the best dose of epoprostenol, the mean PAP further decreased. CONCLUSIONS: In good responders, pulmonary selectivity to epoprostenol is high, and the blood returning to the left-sided heart through the pulmonary circulation increases. Hemodynamics further improve, even after fixing at the best dose of epoprostenol. The present data did not show that an increase in CO precedes lowering of the PAP over the course of improvement.

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BACKGROUND: This study aimed to investigate the annual incidence and characteristics of perioperative pulmonary thromboembolism (PTE) in Japan from 2005 through 2007, and to compare the current trend with that observed in our previous studies conducted since 2002. METHODS: In the 3-year study period, a questionnaire was annually mailed to every institution certified as a training hospital for anesthesiologists by the Japanese Society of Anesthesiologists (JSA). The survey included the parameters of age, sex, type of surgery, and the risk factors in patients who were operated upon. RESULTS: The average rate of effective responses was 55.1%, and a total of 825 cases of perioperative PTE were registered in the 3-year study period. The incidence of perioperative PTE was 2.79 per 10,000 cases in 2005, 2.25 per 10,000 cases in 2006, and 2.57 per 10,000 cases in 2007. The incidence of PTE in all the 3 years was significantly lower than that observed in 2002-03 (P < 0.01). In addition, the incidence of fetal PTE in 2006 and 2007 was also significantly lower than that in 2002-03. The incidence of PTE in older persons (66-85 years) was approximately twice (4.70 per 10,000 cases) and that in the oldest persons (> 86 years) was approximately thrice (6.28 per 10,000 cases) the incidence in middle-aged individuals (2.17 per 10,000 cases). PTE was found to be more frequent in females than in males (males, 1.89 per 10,000 cases; females, 3.75 per 10,000 cases). The types of surgery that most commonly resulted in perioperative PTE were limb and/or hip joint surgery (5.57 per 10,000 cases), thoracotomy with laparotomy (5.19 per 10,000 cases), and spinal surgery (4.49 per 10,000 cases). Perioperative PTE was fatal in 185 patients (22.4%), and the mortality rate of patients who had not received prophylaxis was significantly higher (37.8%) than that of patients who received anticoagulant drugs (20.8%). Guidelines for prevention of perioperative PTE were accepted by 58% of all training institutions. CONCLUSIONS: The incidence of perioperative PTE and fetal PTE has currently decreased; however, prophylaxis with anticoagulant drugs may have reduced the mortality in some cases.

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BACKGROUND: Acute pulmonary embolism (APE) has high mortality. Some APEs with circulatory collapse or cardiopulmonary arrest have been treated by percutaneous cardiopulmonary support (PCPS) in Japan. But there have been no reports with a large number of series of APE treated with the use of PCPS. METHODS AND RESULTS: We collected all the reported cases with acute thrombotic pulmonary embolism treated with PCPS before surgical embolectomy or those without surgical embolectomy in Japan, and assessed the effectiveness of PCPS. PCPS was combined with surgical embolectomy in 35% (68 of 193), thrombolytic therapy in 62% (120/193), and catheter therapy in 24% (46/193). The survival rate treated with PCPS was 73% (80% in surgical embolectomy, 71% in thrombolytic therapy, and 76% in catheter therapy). Logistic regression analysis showed that the mortality rate was elevated in cases with cardiopulmonary arrest (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.52-7.67; p-value, 0.003) but not by surgical embolectomy (OR, 0.99; 95% CI, 0.39-2.53; p-value, 0.98), catheter therapy (OR, 0.71; 95% CI, 0.30-1.72; p-value, 0.45), and thrombolysis (OR, 1.60; 95% CI, 0.64-3.99; p-value, 0.31) as regards to the concomitant therapies with PCPS. CONCLUSION: PCPS might improve the survival rate in APE patients with circulatory collapse or cardiopulmonary arrest, but there was no differences in outcome among cases treated by surgical embolectomy, catheter therapy, and thrombolysis as the concomitant therapies.

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BACKGROUND: There are few data on the differences between deep vein thrombosis (DVT) with pulmonary embolism (PE) (Group A) and without PE (Group B), and no recent data on the incidence of PE and DVT in Japan. METHODS AND RESULTS: The symptoms and findings of the lower extremities and risks for venous thromboembolism were compared between Groups A and B, and the numbers of new patients with PE and those with DVT in 2006 were calculated. DVT was found equally in left and right legs in Group A, but more frequently in left legs than in right legs in Group B. Proximal thrombus was more frequent in Group A than in Group B, and the number of cases of symptoms resulting from DVT was less in Group A than in Group B. Proximal DVT, DVT in the right leg, no symptoms, and younger age were related to the presence of PE. The calculated number of new patients with PE per year was 7,864 (3,492 cases in 1996), and that with DVT per year was 14,674. CONCLUSION: DVT in patients with PE and those without PE differed in the site and symptoms. The calculated number of new patients with PE per year doubled in 1 decade in Japan.

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Microarray analysis demonstrated lung gene encoding osteopontin (OPN), a soluble secreted phosphoprotein, was significantly elevated in rats with hypoxic pulmonary arterial hypertension (PAH). Since OPN enhances vascular smooth muscle cell proliferation, we hypothesized that OPN played a role in the pathogenesis of PAH. Some patients with idiopathic PAH showed increased expression of plasma OPN and lung OPN gene. OPN overexpression in mice caused pronounced pulmonary hypertension and vascular remodeling under hypoxic conditions. A PPARgamma ligand, pioglitazone, which was reported to inhibit OPN gene expression in vitro, attenuated hypoxia-induced increase in lung OPN gene and pulmonary vascular remodeling in rats. These findings indicate that OPN may be responsible for pulmonary vascular remodeling and could be a therapeutic target for PAH.

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The therapeutic effects of phosphodiesterase type 5 inhibitors in patients with pulmonary arterial hypertension (PAH) were reviewed. A double-blind, placebo-controlled study named SUPER-1 showed that sildenafil improved exercise capacity, WHO functional class, hemodynamics, and quality of life. Two randomized, double-blind, crossover studies, showed that sildenafil improved exercise tolerance and quality of life, and reduced estimated pulmonary artery systolic pressure. The dose independent effects of sildenafil on PAH are controversial. There are few case-reports that show vardenafil and tadalafil have benefits in PAH patients. A double-blind study of tadalafil in PAH patients is ongoing.

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BACKGROUND: The pulmonary vascular changes induced by epoprostenol in patients with idiopathic pulmonary artery hypertension (IPAH) have not been reported by a clinical study. METHODS AND RESULTS: Analysis 1 compared the wedged pulmonary angiography (PAG) findings prior to initiation of epoprostenol therapy (n=24) with those after initiation (n=16). Analysis 2 compared the PAG findings prior to and after initiation of epoprostenol therapy (n=9) in the same pulmonary arteries in the same subjects. In analysis 1, a "cotton grass-like" stain originating from the peripheral pulmonary vessels (each vessel could not be distinguished on angiography) was not observable in any of 24 cases before initiation of epoprostenol therapy, but was visible in 13 of 16 cases after (p<0.0001). In analysis 2, the diameter of subsegmental arteries changed from 3.0+/-0.9 mm (mean +/- standard deviation) to 3.7+/-1.2 mm (p=0.004) between the 2 time periods. Cotton grass-like stain was not found in any cases before epoprostenol, but in all 9 cases after chronic use (p=0.004). CONCLUSIONS: After initiating epoprostenol therapy, cotton grass-like stain appeared in most patients with IPAH. The possible reason for this is release of severe vasoconstriction and/or emergence of neovascularization.

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Cases with proximal pulmonary artery aneurysm (PAA) sometimes have severe complications. We report 4 cases of proximal PAA complicated by pulmonary hypertension. Three cases had proximal PAA and one had both proximal and peripheral PAA. Complications associated with proximal PAA are compression of the bronchus, dissection and/or rupture of the pulmonary artery, and thrombus of the pulmonary artery. The available medical treatments have limitations. Two of our patients with proximal PAA are awaiting lung transplantation.

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BACKGROUND: Population-based analysis shows that deaths from pulmonary embolism (PE) are increasing in the older age groups, but it is unclear to what degree PE contributes to death in different ages and gender. METHODS AND RESULTS: Potential contribution factors for all PE and for critical PE (in which PE was the primary cause of death or the main diagnosis) were examined in 396,982 autopsy cases. For all PE, odds ratio (OR) in males was 0.61 (95% confidence interval (CI) 0.59-0.64, p<0.0001), compared with that in females. ORs were 1.10 (95% CI 1.05-1.14, p<0.0001) in 1991-1994 and 1.19 (95% CI 1.14-1.25, p<0.0001) in 1995-1998, compared with those in 1987-1990. ORs for ages 0-9 and 40+ were significantly low compared with that for ages 20-39. For critical PE, similar results were obtained. Pregnancy and/or delivery were found in 38.5% in cases of critical PE in females aged 20-39. CONCLUSION: Compared with other age groups, PE contributed more to deaths in those aged 20-39 years. In recent years, deaths from PE have been slightly but significantly increasing. The incidence of clinically diagnosed critical PE also has been increasing.

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Pulmonary artery aneurysm (PAA), especially the peripheral type, is a rare disease. We report 2 cases of peripheral PAA with pulmonary artery hypertension. Complication associated with peripheral PAA was hemoptysis. Endovascular coil embolization was performed successfully in one patient. The other with peripheral PAA was died of massive hemoptysis. In patients with peripheral PAA, coil embolization is one therapeutic option. We summarized cases with peripheral PAA in Japan.

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BACKGROUND: Septic and amniotic fluid emboli are rare sources of pulmonary embolism (PE), so the present study sought to elucidate the background of these cases. METHODS AND RESULTS: A total of 11,367 PE cases were identified from 396,982 postmortem examinations. The incidence of septic PE was 247 (2.2%) of the total. The origin of infection was found in 85.6% of the cases. Fungal embolus was detected more often than bacterial embolus. The most frequently detected fungus was aspergillus (20.8%). The primary disease associated with fungal embolus was leukemia (43.2%). The incidence of PE cases associated with pregnancy and/or delivery was 89 (0.8%) of the total PE cases. Among them, amniotic fluid embolism was found in 33 (73.3%) of 45 PE cases with vaginal delivery, and in 7 (21.2%) of 33 PE cases with cesarean delivery (p<0.0001). CONCLUSION: Fungal embolus was more frequent than bacterial embolus, and leukemia was most frequent as the primary disease in cases of fungal embolus. The main cause of PE in cesarean section cases was thrombotic embolism, and the main cause in vaginal delivery cases was amniotic fluid embolism.

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There have been no reports on acute pulmonary embolism (APE) after earthquakes. Our aim was to clarify the actual the occurrence of APE following the 2004 Mid Niigata Prefecture earthquake in Japan, and to assess the risk factors for APE after the event. We sent questionnaires to 122 hospitals in the Niigata Prefecture after the earthquake. Cities, towns, and villages in the prefecture were classified into two areas (high evacuee rate area, and low evacuee rate area) due to the mean ratio of evacuees to the overall population during 1 week immediately after the earthquake. A rate of 5% and higher was encountered for the high evacuee rate area and a rate of < 5% was encountered for the low evacuee rate area. Ten out-of-hospital cases of APE (seven in the high evacuee rate area and three in the low evacuee rate area) were diagnosed within the first month after the earthquake. The relative risk of APE was high in the high evacuee rate area (13.09; P = 0.0002) and also higher in women (8.55; P = 0.04). All patients in the high evacuee rate area had stayed in their automobiles for long periods of time, but none had done so in the low evacuee rate area ( P = 0.008).

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Incidence of venous thromboembolism (VTE), which had been considered a relatively rare disease in Japan, has been on the increase in recent years as eating habits have become more similar to those of the West. We have investigated the recent incidence data of perioperative pulmonary thromboembolism (PTE) in Japan and have established guidelines for the prevention of VTE. Recommended thromboprophylaxis is early ambulation for low risk group, elastic stocking (ES) or intermittent pneumatic compression (IPC) for moderate risk group, IPC or low dose unfractionated heparin (LDUH) for high risk group, and LDUH + IPC or LDUH + ES for highest risk group. The management fee for PTE prophylaxis was established and covered by health insurance in April 2004. Surprisingly, the incidence of perioperative PTE decreased just after this guideline was issued. After accumulation of further evidence and application of pharmacological agents, such as low molecular weight heparin, we will establish the advanced guidelines in the future.

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BACKGROUND: The diagnostic and therapeutic strategy for acute pulmonary thromboembolism (APTE) was published by the Japanese Circulation Society. But in Japan, there has been no report on how to improve the pre-test probability in APTE-suspected cases, to determine a practically available diagnostic strategy, nor has been a report that compares diagnostic methods and therapies for APTE by decision analysis. METHODS AND RESULTS: APTE was found in 66.7% before using diagnostic imaging techniques. Compared with the absence of APTE, prolonged immobilization, cancer, tachycardia, unilateral leg swelling and inverted T-wave in V(1-3) were found more often in the presence of APTE. The rate of obtaining the result on the day of ordering the examination test was 100% with arterial blood gas analysis, trans-thoracic echocardiography and computed tomography (CT), 78.2% in D-dimer, 85.5% in pulmonary angiography, and 54.5% in perfusion lung scan. Decision analysis showed that the highest expected utility was anticoagulant over 0.51 in pre-test probability, with CT between 0.13 and 0.51. CONCLUSIONS: The pre-test probability of APTE has already been high before using specific diagnostic imaging techniques in Japan. Our results showed that the diagnostic strategy for APTE made by the Japanese Circulation Society was available in most hospitals in Japan.

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BACKGROUND: The specific incidence of thrombotic pulmonary embolism (PE), tumor PE and tumor invasion into large veins according to tumor type and tumor site remains unclear. METHODS AND RESULTS: A total of 65,181 cancer patients were identified from 98,736 postmortem examinations. Thrombotic PE occurred in 2.32% of all cancer patients and comprised 88.6% of the total number of all PE events. The incidence of thrombotic PE was high in those with adenocarcinoma, leukemia and large cell carcinoma, and was low in those with hepatic cell carcinoma. The incidence of PE was high when tumor was present in hematogenous tissue, lungs, ovaries, pancreas and the biliary system, and was low when tumor was present in the liver. The incidence of tumor PE was high with large cell carcinoma, hepatic cell carcinoma and adenocarcinoma, and was also high when tumor was present in the lungs, ovaries, kidneys and liver. There was a significant correlation between the incidence of tumor PE and the incidence of tumor invasion into large veins. CONCLUSION: The incidence of thrombotic PE, tumor PE and tumor invasion into large veins varies significantly according to tumor histopathology and tumor site.

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BACKGROUND: The potential risk factors for pulmonary thromboembolism (PTE) have not been examined in Japan, so the aims of the present study were to assess independent risk factors for PTE, and to estimate the recent incidence of symptomatic PTE. METHODS AND RESULTS: Based on a mailed questionnaire, the potential risk factors for PTE were prospectively assessed using a matched case - control study, and the number of new patients with PTE in 2004 was calculated prospectively. In multivariate analyses, increase in body mass index (odds ratio (OR) = 2.85 by 10 kg/m2; 95% confidence interval (CI), 1.51-5.39), prolonged immobilization (OR, 8.14; 95% CI, 3.15-20.99), recent major surgery (OR, 6.78; 95% CI, 2.65-17.32), and cancer (OR, 2.72; 95% CI, 1.25-5.95) were identified as independent risk factors for PTE in Japan. The risks for atherosclerosis (diabetes mellitus, hypertension, hyperlipidemia, and smoking), and alcohol consumption did not affect the incidence of PTE. The calculated number of new patients with PTE per year was 4,108 (95% CI, 3,564-4,712) in 2004. CONCLUSION: The independent risk factors for PTE in Japan are body mass index, prolonged immobilization, recent major surgery, and cancer. The number of new patients with PTE in 2004 did not demonstrate an upward trend compared with 2000.

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