Recombinant thrombomodulin attenuates hyper-inflammation and glycocalyx damage in a murine model of Streptococcus pneumoniae-induced sepsis.

PURPOSE: The anticoagulant agent recombinant thrombomodulin (rTM) activates protein C to prevent excessive coagulation and also possibly regulates hyper-inflammation via neutralization of high-mobility-group B1 (HMG-B1). The glycocalyx layer in endothelial cells also plays a pivotal role in preventing septic shock-associated hyperpermeability. The present study examined the effect of rTM in a murine model of Streptococcus pneumoniae-induced sepsis. METHODS: Male C57BL/6N mice were injected intratracheally via midline cervical incision with 2 × 107 CFU of S. pneumoniae (capsular subtype 19A). Control mice were sham-treated identically but injected with saline. rTM (10 mg/kg) was injected intraperitoneally 3 h after septic insult. Blood concentrations of soluble inflammatory mediators (interleukin [IL]-1ß, IL-6, IL-10, and tumor necrosis factor [TNF]-α) were determined using a microarray immunoassay. Serum concentrations of HMG-B1 and syndecan-1, as a parameter of glycocalyx damage, were determined by enzyme-linked immunosorbent assay. The glycocalyx was also evaluated with electron microscopy. The lungs were removed, and digested to cells, which were then stained with a mixture of fluorophore-conjugated antibodies. Anti-mouse primary antibodies included PE-Cy7-conjugated anti-CD31, AlexaFluor 700-conjugated anti-CD45, PerCP-Cy5.5-conjugated anti-CD326, APC-conjugated anti-TNF-α, PE-conjugated anti-IL-6, and PE-conjugated anti-IL-10. A total of 1 × 106 cells per sample were analyzed, and 2 × 105 events were recorded by flow cytometry, and parameters were compared with/without rTM treatment. RESULTS: The blood concentration of TNF-α was significantly reduced 24 h after intratracheal injection in S. pneumoniae-challenged mice treated with rTM (P = 0.016). Levels of IL-10 in the lung endothelium of rTM-treated S. pneumoniae-challenged mice increased significantly 12 h after intratracheal injection (P = 0.03). Intriguingly, serum HMGB-1 and syndecan-1 levels decreased significantly (P = 0.010 and 0.015, respectively) in rTM-treated mice 24 h after intratracheal injection of S. pneumoniae. Electron microscopy indicated that rTM treatment preserved the morphology of the glycocalyx layer in septic mice. CONCLUSIONS: These data suggest that rTM modulates local inflammation in the lung endothelium, thus diminishing systemic inflammation, i.e., hypercytokinemia. Furthermore, rTM treatment reduced serum syndecan-1 levels, thus preventing glycocalyx damage. The use of rTM to treat sepsis caused by bacterial pneumonia could therefore help prevent both excessive inflammation and glycocalyx injury in the lung endothelium.

Cell Tracking Suggests Pathophysiological and Therapeutic Role of Bone Marrow Cells in Sugen5416/Hypoxia Rat Model of Pulmonary Arterial Hypertension.

BACKGROUND: The mechanism of vascular remodelling in pulmonary arterial hypertension (PAH) remains unclear. Hence, defining the origin of cells constituting intractable vascular lesions in PAH is expected to facilitate therapeutic progress. Herein, we aimed to evaluate the origin of intractable vascular lesions in PAH rodent models via bone marrow (BM) and orthotopic lung transplantation (LT). METHODS: To trace BM-derived cells, we prepared chimeric rats transplanted with BM cells from green fluorescent protein (GFP) transgenic rats. Male rats were transplanted with lungs obtained from female rats and vice versa. Pulmonary hypertension was induced in the transplanted rats via Sugen5416 treatment and subsequent chronic hypoxia (Su/Hx). RESULTS: In the chimeric Su/Hx models, GFP-positive cells were observed in the pulmonary vascular area. Moreover, the right ventricular systolic pressure was significantly lower compared with wild-type Su/Hx rats without BM transplantation (P = 0.009). PAH suppression was also observed in rats that received allograft transplanted BM transplantation. In male rats that received LT and Su/Hx, BM-derived cells carrying the Y chromosome were also detected in neointimal occlusive lesions of the transplanted lungs received from female rats. CONCLUSIONS: BM-derived cells participate in pulmonary vascular remodelling in the Su/Hx rat model, whereas BM transplantation may contribute to suppression of development of PAH.

Nocturnal Hypoxemia and High Circulating TNF-α Levels in Chronic Thromboembolic Pulmonary Hypertension.

Objective Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by persistent thromboemboli of the pulmonary arteries, and one of its etiological factors may be inflammation. Sleep disordered breathing (SDB) is reportedly an important complication of pulmonary hypertension. However, the association between SDB and inflammation in CTEPH has been undefined. This prospective observational study analyzed the association between the severity of SDB, pulmonary hemodynamic parameters and the systemic inflammation level in patients with CTEPH. Methods CTEPH patients admitted for a right heart catheter (RHC) examination were consecutively enrolled from November 2017 to June 2019 at the pulmonary hypertension center in Chiba University Hospital. Patients with idiopathic pulmonary arterial hypertension (IPAH) were also enrolled as a control group. All patients underwent a sleep study using a WatchPAT 200 during admission. Results The CTEPH patients showed worse nocturnal hypoxemia, oxygen desaturation index (ODI), and apnea-hypopnea index than the IPAH patients. Among these factors, only the nocturnal mean percutaneous oxygen saturation (SpO2) was negatively correlated with the pulmonary hemodynamic parameters. The circulating tumor necrosis factor-alpha (TNF-α) level was also high in the CTEPH group, and a multivariate analysis showed that the nocturnal mean SpO2 was the most important predictive factor for a high TNF-α level. Conclusion We showed that CTEPH patients had high serum TNF-α levels and that the nocturnal mean SpO2 was a predictive factor for serum TNF-α levels. Further investigations focused on nocturnal hypoxemia and the TNF-α level may provide novel insight into the etiology and new therapeutic strategies for CTEPH.

Characteristics of Japanese elderly patients with pulmonary arterial hypertension.

Previous nationwide Japanese data suggested that pulmonary arterial hypertension (PAH) predominantly affects young women. However, the number of elderly patients diagnosed with PAH has been increasing in western countries. There have been no reports on elderly PAH patients in Asian countries. This study aimed to investigate the clinical characteristics of elderly PAH patients in a Japanese cohort. Idiopathic/heritable PAH (I/H-PAH) was included in the national research project on intractable diseases. The patients were required to submit a clinical research form completed by their attending physicians. We analyzed the characteristics of Japanese I/H-PAH using the newly registered forms in 2013 (Study 1, n = 148). Also, we did a retrospective, observational cohort study at Chiba University Hospital (Study 2, n = 42). We compared the characteristics of elderly PAH patients (≥65 years old) with younger patients (<65) in both studies. Study 1 revealed a predominance of males (51% male), better hemodynamics and poorer exercise capacity in the elderly group (n = 72), compared with the younger group (n = 76) in study 1. In Study 2, elderly patients showed a male predominance (63% male), a higher ratio of smokers, a lower % carbon monoxide diffusing capacity, and poorer exercise tolerance. Elderly patients in Study 2 showed less improvement in hemodynamics with therapy. There was no significant difference in disease-specific survival between elderly and younger patients. Japanese elderly patients with I/H-PAH showed poorer exercise capacity and impaired gas exchange, but better pulmonary hemodynamics than younger patients.

Protective role of endothelial progenitor cells stimulated by riociguat in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Pulmonary endothelial damage has a negative impact on the maintenance of normal pulmonary vascular function. Such damage results in delayed thrombus dissolution and vascular remodeling in chronic thromboembolic pulmonary hypertension (CTEPH). Although endothelial progenitor cells (EPCs) may be incorporated into neovasculature during vascular repair, their function in CTEPH remains unclarified, especially under the augmentation of soluble guanylate cyclase (sGC) activity. METHODS AND RESULTS: We evaluated the effect of EPCs on endothelial function and compared the effect of riociguat, a sGC stimulator, on the number and function of circulating EPCs in two groups of CTEPH patients. The two groups consisted 16 CTEPH patients who were treatment naïve (Naïve group), and 14 CTEPH patients who were being treated with riociguat, a sGC stimulator (Riociguat group). The number of circulating EPCs in the Riociguat group was significantly higher than that in the Naïve group. Gene expression levels associated with angiogenesis were significantly higher in EPCs of the Riociguat group. EPC-stimulated tube formation and migration of human pulmonary microvascular endothelial cell (hPMVEC) in the Riociguat group exceeded that in the Naïve group. The angiogenic ability of hPMVECs stimulated by EPCs in the Riociguat group was enhanced compared to that of the sGC stimulator, BAY 41-2272. CONCLUSION: These findings indicate that riociguat may induce EPCs to play a protective role via modulation of endothelial functions associated with CTEPH. TRANSLATION ASPECT OF THE WORK: Endothelial dysfunction exacerbates CTEPH. Riociguat enhanced the protective role of EPCs via neovascularization, which prevented vascular remodeling and alleviated CTEPH.

Pulmonary hypertension with a low cardiac index requires a higher PaO2 level to avoid tissue hypoxia.

BACKGROUND AND OBJECTIVE: The optimal oxygen supplementation needed to avoid tissue hypoxia in patients with pulmonary hypertension (PH) remains unclear. This study aimed to identify the arterial oxygen tension (PaO2 ) level needed to avoid tissue hypoxia which results in a poor prognosis in patients with PH. METHODS: We retrospectively analysed the data for 1571 right heart catheterizations in patients suspected of having PH between 1983 and 2017 at our institution. Examinations were classified according to mean pulmonary arterial pressure (mPAP), cardiac index (CI) and the presence of lung disease, pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH). The PaO2 levels needed to avoid tissue hypoxia were compared in each subgroup. RESULTS: The estimated PaO2 equivalent to a mixed venous oxygen tension (PvO2 ) of 35 mm Hg (tissue hypoxia) was 63.2 mm Hg in all patients, 77.0 mm Hg in those with decreased CI (<2.5 L/min/m2 ) and 57.0 mm Hg in those with preserved CI. Multivariate regression analysis identified mPAP, CI and PaO2 to be independent predictors of extremely low PvO2 . Similar results were observed regardless of the severity of PH or the presence of lung disease, PAH or CTEPH. The PaO2 level needed to avoid tissue hypoxia was higher in patients with mild PH and decreased CI than in those with severe PH and preserved CI (70.2 vs 61.5 mm Hg). CONCLUSION: These findings indicate that a decreased CI rather than increased mPAP induces tissue hypoxia in PH. Patients with PH and decreased CI may need adjustment of oxygen therapy at higher PaO2 levels compared with patients with preserved CI.

Involvement of pulmonary arteriopathy in the development and severity of reperfusion pulmonary edema after pulmonary endarterectomy.

Reperfusion pulmonary edema (RPE) is a common complication after pulmonary endarterectomy (PEA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, the precise mechanisms underlying the development of RPE remain unclear. To evaluate the effects of pulmonary vasculopathy on RPE, the severity of the pulmonary arteriopathies and venopathies of lung tissues biopsied during PEA were pathologically quantified in 33 CTEPH patients. The severity of RPE was classified from grade 0 (no RPE) to 4 (death due to RPE) based on the arterial oxygen tension/inspiratory oxygen fraction (P/F ratio) and necessity of respiratory management. Among the 33 patients (27 women; mean age = 63.3 years), 17 (51.5%) patients developed RPE. The severity of pulmonary arteriopathy (obstruction ratio) correlated with the grade of RPE (r = 0.576, P = 0.0005). The obstruction ratio also correlated with the P/F ratio (r = -0.543, P = 0.001) and the perioperative mean pulmonary arterial pressure (r = 0.445, P = 0.009). Multivariate logistic regression analysis revealed that the obstruction ratio was a significant independent determinant for the development of RPE (odds ratio = 15.7; 95% confidence interval = 2.29-108.00, P = 0.005). In conclusion, pulmonary arteriopathy could be a determinant of the development and severity of RPE after PEA.

Effectiveness of pulmonary vasodilators on pulmonary hypertension associated with POEMS syndrome.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare plasma cell disease. Patients with POEMS syndrome are considered to be at a high risk of developing pulmonary hypertension (PH). We report a 51-year-old woman diagnosed with PH associated with POEMS syndrome. She was started on dexamethasone and thalidomide. Although, the plasma vascular endothelial growth factor (VEGF) level decreased, systolic pulmonary artery pressure (sPAP) remained high. Auto-peripheral blood stem cell transplantation improved the plasma VEGF and sPAP levels. Four years later, she presented with dyspnoea on exertion, and elevated plasma VEGF and sPAP levels. Subsequently, on administering sildenafil and macitentan, the plasma VEGF and PH levels improved. Pulmonary vasodilators can be considered when PH remains after treatment of POEMS syndrome.

Clinical characteristics and prognosis in patients with chronic thromboembolic pulmonary hypertension and a concomitant psychiatric disorder.

Chronic thromboembolic pulmonary hypertension (CTEPH) can cause right heart failure. A concomitant psychiatric disorder (PD) is thought to increase the risk of acute pulmonary thromboembolism; however, whether PDs are associated with deterioration in CTEPH pathophysiology is unclear. In this study, we evaluated the clinical characteristics and prognoses in patients with CTEPH and a co-existing PD. We retrospectively identified 229 consecutive patients (mean age = 58.7 ± 12.5 years; 160 women) with CTEPH and categorized them according to whether they had a PD (PD group; n = 22, 9.7%) or not (non-PD group; n = 207, 90.3%). We compared the clinical characteristics, respiratory function, hemodynamics, and clinical courses in the two groups. Those in the PD group had significantly lower exercise tolerance compared to the non-PD group (6-min walk test, 309.5 ± 89.5 m vs. 369.4 ± 97.9 m, P = 0.008, percent vital capacity 85.5% ± 17.3% vs. 96.0% ± 15.5%, P = 0.003) and partial pressure of oxygen (PaO2) (54.4 ± 8.6 mmHg vs. 59.3 ± 10.7 mmHg, P = 0.039). Three-year survival was significantly poorer in the PD group compared to the non-PD group (66.1% vs 89.7%, P = 0.0026, log-rank test), particularly in patients who underwent surgery (62.2% vs 89.5%, P < 0.001, log-rank test). A concomitant PD was associated with low exercise tolerance and impaired respiratory function in patients with CTEPH and predicted poor survival, especially in those who underwent a pulmonary endarterectomy.

Partial anomalous pulmonary venous return with dual drainage to the superior vena cava and left atrium with pulmonary hypertension.

Partial anomalous pulmonary venous return (PAPVR) is a rare congenital cardiovascular anomaly. A 68-year-old woman was referred to our hospital for detailed examination for pulmonary hypertension (PH). She had been diagnosed as having pulmonary artery dilation and suspected to have PH during a health check seven years prior. A contrast computed tomography showed that the right upper pulmonary vein (RUPV) returned to the superior vena cava (SVC) with a preserved normal connection to the left atrium (LA). Surgical repair was performed. We reported an extremely rare case of isolated PAPVR with PH showing dual drainage into the SVC and LA.

Long-Term Outcome of Chronic Thromboembolic Pulmonary Hypertension at a Single Japanese Pulmonary Endarterectomy Center.

BACKGROUND: Several new treatments for chronic thromboembolic pulmonary hypertension (CTEPH) have appeared in recent years, which have led to changes in the treatment algorithm. Changes in survival rates and prognostic factors, however, have not been estimated so far.Methods and Results:Two hundred and eighty patients were diagnosed with CTEPH at Chiba University Hospital between June 1986 and June 2016. Survival rate was investigated by date of treatment initiation (group 1, 1986-1998; group 2, 1999-2008; group 3, 2009-2016). Survival rates were also evaluated by treatment strategy: balloon pulmonary angioplasty (BPA), pulmonary endarterectomy (PEA), and medical treatment. Group 3 had significantly better disease-specific survival than groups 1 and 2 (5-year survival: 91.9% vs. 67.1%, 77.0%, respectively). For the non-PEA (BPA+medication) strategy, group 3 had better disease-specific survival than groups 1 and 2 (5-year survival: 94.9% vs. 54.6%, 74.2%, respectively). The PEA strategy had significantly better survival than the medication strategy in groups 1 and 2, whereas no difference was observed between the BPA, PEA, and medication strategies in group 3. CONCLUSIONS: Survival in CTEPH in the recent era has significantly improved, especially in non-PEA patients. BPA and selective pulmonary vasodilators could improve survival in the non-PEA group. In the present study, no difference in survival was found between PEA and non-PEA.

Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension.

Endothelial-to-mesenchymal transition (EndMT) is a process in which endothelial cells lose polarity and cell-to cell contacts, and undergo a dramatic remodeling of the cytoskeleton. It has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). However, the characteristics of cells which have undergone EndMT cells in vivo have not been reported and so remain unclear. To study this, sugen5416 and hypoxia (SuHx)-induced PAH was established in Cdh5-Cre/Gt(ROSA)26Sortm4(ACTB-tdTomato,EGFP)Luo/J double transgenic mice, in which GFP was stably expressed in pan-endothelial cells. After 3 wk of SuHx, flow cytometry and immunohistochemistry demonstrated CD144-negative and GFP-positive cells (complete EndMT cells) possessed higher proliferative and migratory activity compared with other mesenchymal cells. While CD144-positive and α-smooth muscle actin (α-SMA)-positive cells (partial EndMT cells) continued to express endothelial progenitor cell markers, complete EndMT cells were Sca-1-rich mesenchymal cells with high proliferative and migratory ability. When transferred in fibronectin-coated chamber slides containing smooth muscle media, α-SMA robustly expressed in these cells compared with cEndMT cells that were grown in maintenance media. Demonstrating additional paracrine effects, conditioned medium from isolated complete EndMT cells induced enhanced mesenchymal proliferation and migration and increased angiogenesis compared with conditioned medium from resident mesenchymal cells. Overall, these findings show that EndMT cells could contribute to the pathogenesis of PAH both directly, by transformation into smooth muscle-like cells with higher proliferative and migratory potency, and indirectly, through paracrine effects on vascular intimal and medial proliferation.

Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition.

BACKGROUND: Pulmonary fibrosis is a late manifestation of acute respiratory distress syndrome (ARDS). Sepsis is a major cause of ARDS, and its pathogenesis includes endotoxin-induced vascular injury. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play an important role in pulmonary fibrosis. On the other hand, dipeptidyl peptidase (DPP)-4 was reported to improve vascular dysfunction in an experimental sepsis model, although whether DPP-4 affects EndMT and fibrosis initiation during lipopolysaccharide (LPS)-induced lung injury is unclear. The aim of this study was to investigate the anti-EndMT effects of the DPP-4 inhibitor vildagliptin in pulmonary fibrosis after systemic endotoxemic injury. METHODS: A septic lung injury model was established by intraperitoneal injection of lipopolysaccharide (LPS) in eight-week-old male mice (5 mg/kg for five consecutive days). The mice were then treated with vehicle or vildagliptin (intraperitoneally, 10 mg/kg, once daily for 14 consecutive days from 1 day before the first administration of LPS.). Flow cytometry, immunohistochemical staining, and quantitative polymerase chain reaction (qPCR) analysis was used to assess cell dynamics and EndMT function in lung samples from the mice. RESULTS: Lung tissue samples from treated mice revealed obvious inflammatory reactions and typical interstitial fibrosis 2 days and 28 days after LPS challenge. Quantitative flow cytometric analysis showed that the number of pulmonary vascular endothelial cells (PVECs) expressing alpha-smooth muscle actin (α-SMA) or S100 calcium-binding protein A4 (S100A4) increased 28 days after LPS challenge. Similar increases in expression were also confirmed by qPCR of mRNA from isolated PVECs. EndMT cells had higher proliferative activity and migration activity than mesenchymal cells. All of these changes were alleviated by intraperitoneal injection of vildagliptin. Interestingly, vildagliptin and linagliptin significantly attenuated EndMT in the absence of immune cells or GLP-1. CONCLUSIONS: Inhibiting DPP-4 signaling by vildagliptin could ameliorate pulmonary fibrosis by downregulating EndMT in systemic LPS-induced lung injury.

Endothelial cell-related autophagic pathways in Sugen/hypoxia-exposed pulmonary arterial hypertensive rats.

Pulmonary arterial hypertension (PAH) is characterized by progressive obstructive remodeling of pulmonary arteries. However, no reports have described the causative role of the autophagic pathway in pulmonary vascular endothelial cell (EC) alterations associated with PAH. This study investigated the time-dependent role of the autophagic pathway in pulmonary vascular ECs and pulmonary vascular EC kinesis in a severe PAH rat model (Sugen/hypoxia rat) and evaluated whether timely induction of the autophagic pathway by rapamycin improves PAH. Hemodynamic and histological examinations as well as flow cytometry of pulmonary vascular EC-related autophagic pathways and pulmonary vascular EC kinetics in lung cell suspensions were performed. The time-dependent and therapeutic effects of rapamycin on the autophagic pathway were also assessed. Sugen/hypoxia rats treated with the vascular endothelial growth factor receptor blocker SU5416 showed increased right ventricular systolic pressure (RVSP) and numbers of obstructive vessels due to increased pulmonary vascular remodeling. The expression of the autophagic marker LC3 in ECs also changed in a time-dependent manner, in parallel with proliferation and apoptotic markers as assessed by flow cytometry. These results suggest the presence of cross talk between pulmonary vascular remodeling and the autophagic pathway, especially in small vascular lesions. Moreover, treatment of Sugen/hypoxia rats with rapamycin after SU5416 injection activated the autophagic pathway and improved the balance between cell proliferation and apoptosis in pulmonary vascular ECs to reduce RVSP and pulmonary vascular remodeling. These results suggested that the autophagic pathway can suppress PAH progression and that rapamycin-dependent activation of the autophagic pathway could ameliorate PAH.

Riociguat for patients with chronic thromboembolic pulmonary hypertension: Usefulness of transitioning from phosphodiesterase type 5 inhibitor.

BACKGROUND: Riociguat, the first approved drug for patients with chronic thromboembolic pulmonary hypertension (CTEPH), is a soluble guanylate cyclase (sGC) Stimulator. It directly stimulates sGC independently of nitric oxide (NO) and increases sGC sensitivity for NO. The safety and efficacy of transitioning from a phosphodiesterase 5 inhibitor (PDE5i) to riociguat is unknown. METHODS AND RESULTS: Twenty-three patients were prospectively enrolled: 8 symptomatic patients with inadequate clinical responses to PDE5i were changed to riociguat (transitioned group); 15 started riociguat anew (new or add-on group). We analyzed the change from baseline to 6-12 months of riociguat treatment for the 6-minute walk distance (6MWD), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI), partial pressure of oxygen in arterial blood (PaO2), brain natriuretic peptide (BNP), World Health Organization (WHO) functional class, safety and adverse events. The mPAP, BNP and WHO functional class significantly improved in total. In the transitioned group, BNP significantly decreased by -116.5±188.6pg/ml (P=0.0156). The 6MWD, mPAP, PVR, CI, and PaO2 improved but not significantly. The baseline condition was significantly more severe in the transitioned than in the new or add-on group. No patients discontinued riociguat. Relatively rapid transitioning from PDE5i to riociguat was safe under careful observation. CONCLUSIONS: Transitioning to riociguat may be safe and effective in CTEPH patients with inadequate clinical responses to PDE5i.

The dilatation of main pulmonary artery and right ventricle observed by enhanced chest computed tomography predict poor outcome in inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Dilatation of the pulmonary artery and right ventricle on chest computed tomography images is often observed in patients with pulmonary hypertension. The clinical significance of these image findings has not been defined in chronic thromboembolic pulmonary hypertension. We investigated whether the pulmonary arterial and right ventricle dilatation was associated with poor outcome in chronic thromboembolic pulmonary hypertension. METHODS: This was a retrospective cohort investigation in 60 subjects with inoperable chronic thromboembolic pulmonary hypertension diagnosed consecutively between 1997 and 2010 at Chiba University Hospital. Digital scout multi-detector chest computed tomography images were obtained. The main pulmonary arterial to ascending aortic diameter ratio and the right ventricular to left ventricular diameter ratio were calculated. RESULTS: Main pulmonary arterial to ascending aortic diameter ratio ranged from 0.85 to 1.84, and right ventricular to left ventricular diameter ratio ranged from 0.71 to 2.88. During the observation period of 1284.5days (range, 21-4550days), 13 patients required hospitalization due to worsening; 6 of them died. Kaplan-Meier analysis showed significant differences in hospitalization between the patients with main pulmonary arterial to ascending aortic diameter ratio of ≥1.1 and <1.1 (log-rank test, p=0.014) and between the patients with right ventricular to left ventricular diameter ratio of ≥1.2 and <1.2 (log-rank test, p=0.013). There was a significant difference in the prognosis between the patients with RV/LV ratio≥1.2 and those with RV/LV ratio<1.2 (log-rank test, p=0.033). CONCLUSIONS: Main pulmonary arterial to ascending aortic diameter ratio measured using enhanced CT images was associated with the risk for first clinical exacerbation, and right ventricular to left ventricular diameter ratio was associated with the risk for poor prognosis in inoperable chronic thromboembolic pulmonary hypertension.

The anticoagulant effects of warfarin and the bleeding risk associated with its use in patients with chronic thromboembolic pulmonary hypertension at a specialist center in Japan: a retrospective cohort study.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) require lifelong anticoagulation therapy. However, the bleeding risk and recurrence of venous thromboembolism (VTE) in CTEPH patients who are administered warfarin have not been adequately evaluated. The purpose of this study was to evaluate the risk of clinically relevant bleeding, recurrent VTE, and clinical worsening in patients with CTEPH who were administered warfarin. The clinical records of 72 patients with CTEPH who regularly visited our institution and were administered warfarin were retrospectively reviewed between 1 January 2011 and 31 December 2015. We investigated the incidence of clinically relevant bleeding events, recurrent VTE, and hospitalization for the deterioration of pulmonary hypertension or right heart failure (RHF) during the observation period. The mean observation period for the 72 patients was 3.60 ± 1.60 person-years. Clinically relevant bleeding, RHF, and recurrent VTE occurred in 21 (29.2%), eight (11.1%), and three (4.2%) of 72 patients, respectively, and the incidence rates for these events were 8.1%/person-year, 3.1%/person-year, and 1.2%/person-year, respectively. The incidence rates for the major and non-major bleeding events were 5.0%/person-year and 3.9%/person-year, respectively. The incidence of clinically relevant bleeding events was 20.8%/person-year during medical treatment with a soluble guanylate cyclase stimulator. One of 35 patients (2.9%) during the post-pulmonary endarterectomy period experienced hemoptysis during observation period (> 6 months after pulmonary endarterectomy). No bleeding events occurred during the post-balloon pulmonary angioplasty period. In conclusion, warfarin effectively prevents VTE recurrence in CTEPH patients, but its effects may be associated with a considerable bleeding risk.

Repeated Diffuse Alveolar Hemorrhage in a Patient with Hemophilia B.

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication that occurs in association with various diseases including coagulation disorders. In rare cases, it is caused by hemophilia. A 48-year-old man was admitted to our hospital for a third time due to DAH. Although the cause of DAH could not be identified by bronchoscopy or laboratory tests, a good response to corticosteroids suggested idiopathic DAH with pulmonary capillaritis. The patient was diagnosed with hemophilia B based on the results of a detailed inquiry, a mildly prolonged activated partial thromboplastin time, and low factor IX activity. Hemophilia may be an underlying factor that exacerbates the bleeding of patients with DAH, even when they show a good response to corticosteroids.

Prognostic and pathophysiological marker for patients with chronic thromboembolic pulmonary hypertension: Usefulness of diffusing capacity for carbon monoxide at diagnosis.

BACKGROUND AND OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease in some patients, despite improved treatments. Microvasculopathy has been implicated in the poor outcomes of patients with CTEPH. A reduction in the diffusing capacity for carbon monoxide (DLCO ) was previously suggested to indicate microvasculopathy in CTEPH patients; therefore, we assessed DLCO /alveolar ventilation (DLCO /VA ) as a prognostic and pathophysiological marker in CTEPH. METHODS: We performed a retrospective cohort study of 214 CTEPH patients consecutively diagnosed between 1986 and 2011. After exclusion of 24 patients because of missing DLCO data or severe obstructive impairment, the mortality rates of medically treated patients classified with normal or decreased DLCO values were compared, and prognostic factors were determined. The relationship between long-term surgical outcomes and DLCO /VA was also investigated. RESULTS: Ninety-one inoperable patients were treated medically, two of whom underwent balloon pulmonary angioplasty. Ninety-nine underwent pulmonary endarterectomy. The 5-year survival rate of medically treated patients was significantly lower in patients with decreased DLCO /VA than in those with normal values (61.4% vs 90.4%, P = 0.017). Decreased preoperative DLCO /VA was associated with a smaller percent decrease in post-operative pulmonary vascular resistance, but not with the extent of proximal thrombi; these results may support our hypothesis that DLCO reflects microvascular involvement. CONCLUSION: Decreased DLCO /VA was associated with poor outcomes of medically treated CTEPH patients; and may be useful for identifying high-risk patients, potentially leading to earlier and more appropriate interventions.