関根 亜由美

BACKGROUND: Pulmonary arterial hypertension is a serious medical condition. However, the condition is often misdiagnosed or a rather long delay occurs from symptom onset to diagnosis, associated with decreased 5-year survival. In this study, we developed and tested a deep-learning algorithm to detect pulmonary arterial hypertension using chest X-ray (CXR) images. METHODS: From the image archive of Chiba University Hospital, 259 CXR images from 145 patients with pulmonary arterial hypertension and 260 CXR images from 260 control patients were identified; of which 418 were used for training and 101 were used for testing. Using the testing dataset for each image, the algorithm outputted a numerical value from 0 to 1 (the probability of the pulmonary arterial hypertension score). The training process employed a binary cross-entropy loss function with stochastic gradient descent optimization (learning rate parameter, α = 0.01). In addition, using the same testing dataset, the algorithm's ability to identify pulmonary arterial hypertension was compared with that of experienced doctors. RESULTS: The area under the curve (AUC) of the receiver operating characteristic curve for the detection ability of the algorithm was 0.988. Using an AUC threshold of 0.69, the sensitivity and specificity of the algorithm were 0.933 and 0.982, respectively. The AUC of the algorithm's detection ability was superior to that of the doctors. CONCLUSION: The CXR image-derived deep-learning algorithm had superior pulmonary arterial hypertension detection capability compared with that of experienced doctors.

The percentage cross-sectional area of the lung under five (%CSA<5) is the percentage of pulmonary vessels with <5 mm2 area relative to the total lung area on computed tomography (CT). The extent that %CSA<5 is related to pulmonary hemodynamics in patients with chronic thromboembolic pulmonary hypertension (CTEPH) is unclear, as is the effect of pulmonary endarterectomy (PEA) on %CSA<5. Therefore, we aimed to evaluate the clinical significance of %CSA<5 in patients with CTEPH. We studied 98 patients (64 females, mean age 62.5 ± 11.9 years), who underwent CT with %CSA<5 measurement and right heart catheterization (RHC). Patients were classified into groups based on eligibility for PEA. We compared the %CSA<5 with pulmonary hemodynamics measured by RHC in various groups. In 38 patients who underwent PEA, the relationship between %CSA<5 and pulmonary hemodynamics was also evaluated before and after PEA. Significant correlations between %CSA<5 and pulmonary vascular resistance, and compliance, and pulmonary artery pulse pressure were observed in all patients. Pulmonary hemodynamics in the patients who underwent or were eligible for PEA showed a significant correlation with %CSA<5. Additionally, %CSA<5 was significantly lower in the postoperative than in the preoperative group. There was no correlation between changes in %CSA<5 and pulmonary hemodynamics before and after PEA. Furthermore, %CSA<5 did not correlate significantly with prognosis. %CSA<5 may reflect pulmonary hemodynamics in CTEPH with central thrombosis. Furthermore, %CSA<5 was reduced by PEA postoperatively. However, %CSA<5 is not a prognostic indicator, its clinical usefulness in CTEPH patients is limited, and further validation is required.

Residual pulmonary hypertension (PH) negatively impacts long-term results following pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). We sought to reveal whether modern PH therapy with PH-targeted medicine and balloon pulmonary angioplasty (BPA) improved long-term results of residual PH after PEA. Long-term findings of 80 patients who survived PEA between 2011 and 2019 were retrospectively investigated. One month after PEA, 30 patients developed residual PH defined as mean pulmonary artery pressure (mPAP) ≥25 mmHg, of whom 23 were treated by PH-targeted medicine and 9 by BPA. Patients with residual PH acquired considerably better functional status and exercise capacity after PEA, however, exhibited significantly worse survival rates than those without. Eleven patients died during follow-up: 8 patients with residual PH and 3 controls. Among patients with residual PH, the deceased had a significantly lower %decrease in mPAP from 1 month to 1 year following PEA (7.4 [-32.6 to 8.0] % vs. 10.4 [3.7-27.8] %, p = 0.03) and higher mPAP at 1 year following PEA (39.5 [33.25-42.5] vs. 27 [26-34] mmHg, p < 0.01) despite PH-targeted medicine than the survived. No patients passed away from right heart failure, and there was no difference between the groups in CTEPH-related mortality. Modern PH therapy was used to address the majority of residual PH. Long-term survival after PEA was negatively impacted by residual PH, but it appeared that long-term mortality was also correlated with unrelieved residual PH despite PH-targeted medicine. Modern PH therapy may have enhanced functional status and excercise capacity, and averted fatal right heart failure.

RNF213 p.Arg4810Lys is linked to various vascular diseases, including pulmonary arterial hypertension (PAH); however, its pathogenesis remains unclear. Here, we report the unique features of two cases of severe PAH with this variant: one is the first reported case with stenosis of the thoracic and abdominal aorta, femoral arteries, and subclavian veins. Coexistence of severe and continuous eosinophilic inflammation, which has been suspected to be implicated in the pathogenesis of PAH in previous fundamental studies, was also present in both cases. Further studies are needed to clarify the pathogenetic mechanisms in vascular lesions with this variant.

Abstract Background The prognostic value of mixed venous oxygen tension (PvO₂) at pulmonary hypertension diagnosis treated with selective pulmonary vasodilators remains unclear. This study sought to investigate the association of PvO₂ with long-term prognosis in pulmonary arterial hypertension (PAH) and medically treated chronic thromboembolic pulmonary hypertension (CTEPH) and to identify the distinct mechanisms influencing tissue hypoxia in patients with CTEPH or PAH. Methods We retrospectively analyzed data from 138 (age: 50.2 ± 16.6 years, 81.9% women) and 268 (age: 57.4 ± 13.1 years, 72.8% women) patients with PAH and CTEPH, respectively, diagnosed at our institution from 1983 to 2018. We analyzed the survival rates of patients with/without tissue hypoxia (PvO₂ &lt; 35 mmHg) and identified their prognostic factors based on the pulmonary hypertension risk stratification guidelines. Results Survival was significantly poorer in patients with tissue hypoxia than in those without it for PAH (P = 0.001) and CTEPH (P = 0.017) treated with selective pulmonary vasodilators. In patients with PAH, PvO₂ more strongly correlated with prognosis than other hemodynamic prognostic factors regardless of selective pulmonary vasodilators usage. PvO₂ was the only significant prognostic factor in patients with CTEPH treated with pulmonary hypertension medication. Patients with CTEPH experiencing tissue hypoxia exhibited significantly poorer survival than those in the intervention group (P &lt; 0.001). PvO₂ more strongly correlated with the cardiac index (CI) than the alveolar-arterial oxygen gradient (A-aDO₂) in PAH; whereas in CTEPH, PvO₂ was more strongly correlated with A-aDO₂ than with CI. Conclusions PvO₂ may represent a crucial prognostic factor for pulmonary hypertension. The prognostic impact of tissue hypoxia affects different aspects of PAH and CTEPH, thereby reflecting their distinct pathogenesis.

PURPOSE: Neurologic adverse events (NAEs) are a major complication after pulmonary endarterectomy (PEA) performed under periods of deep hypothermic circulatory arrest (HCA) for chronic thromboembolic pulmonary hypertension. We modified the PEA strategy to prevent NAEs and evaluated the effectiveness of these modifications. METHODS: We reviewed the surgical outcomes of 87 patients divided into the following three groups based on the surgical strategy used: group S (n = 49), periods of deep HCA with alpha-stat strategy; group M1 (n = 19), deep HCA with modifications of slower cooling and rewarming rates and the pH-stat strategy for cooling: and group M2 (n = 13), multiple short periods of moderate HCA. RESULTS: PEA provided significant improvement of pulmonary hemodynamics in each group. Sixteen (29%) of the 49 group S patients suffered NAEs, associated with total circulatory arrest time (cutoff, 57 min) and Jamieson type I disease. The Group M1 and M2 patients did not suffer NAEs, although the group M1 patients had prolonged cardiopulmonary bypass (CPB) and more frequent respiratory failure. CONCLUSIONS: NAEs were common after PEA performed under periods of deep HCA. The modified surgical strategy could decrease the risk of NAEs but increase the risk of respiratory failure. Multiple short periods of moderate HCA may be useful for patients at risk of NAEs.

Abstract Background The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is considered to be associated with chronic inflammation; however, the underlying mechanism remains unclear. Recently, altered gut microbiota were found in patients with pulmonary arterial hypertension (PAH) and in experimental PAH models. The aim of this study was to characterize the gut microbiota in patients with CTEPH and assess the relationship between gut dysbiosis and inflammation in CTEPH. Methods In this observational study, fecal samples were collected from 11 patients with CTEPH and 22 healthy participants. The abundance of gut microbiota in these fecal samples was assessed using 16S ribosomal ribonucleic acid (rRNA) gene sequencing. Inflammatory cytokine and endotoxin levels were also assessed in patients with CTEPH and control participants. Results The levels of serum tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1α were elevated in patients with CTEPH. Plasma endotoxin levels were significantly increased in patients with CTEPH (P &lt; 0.001), and were positively correlated with TNF-α, IL-6, IL-8, and MIP-1α levels. The 16S rRNA gene sequencing and the principal coordinate analysis revealed the distinction in the gut microbiota between patients with CTEPH (P &lt; 0.01) and control participants as well as the decreased bacterial alpha-diversity in patients with CTEPH. A random forest analysis for predicting the distinction in gut microbiota revealed an accuracy of 80.3%. Conclusion The composition of the gut microbiota in patients with CTEPH was distinct from that of healthy participants, which may be associated with the elevated inflammatory cytokines and endotoxins in CTEPH.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension caused by persistent thromboembolism of the pulmonary arteries. In clinical practice, CTEPH patients often show obstructive ventilatory impairment, even in the absence of a smoking history. Recent reports imply a tendency for CTEPH patients to have a lower FEV1.0; however, the mechanism underlying obstructive impairment remains unknown. METHODS: We retrospectively analyzed CTEPH patients who underwent a pulmonary function test and respiratory impedance test to evaluate their exertional dyspnea during admission for right heart catheterization from January 2000 to December 2019. We excluded patients with a smoking history to rule out the effect of smoking on obstructive impairment. RESULTS: A total of 135 CTEPH patients were analyzed. The median FEV1.0/FVC was 76.0%, %FEV 1.0 had a negative correlation with the mean pulmonary artery pressure and pulmonary vascular resistance and the CT Angiogram (CTA) obstruction score. A multivariate regression analysis revealed that the CTA obstruction score was an independent factor of a lower %FEV1.0. In the 54 patients who underwent pulmonary endarterectomy, %FEV1.0 was improved in some cases and was not in some. Mean PAP largely decreased after PEA in the better %FEV1.0 improved cases, suggesting that vascular involvement in CTEPH could be associated with spirometry obstructive impairment. CONCLUSION: %FEV1.0 had a significant correlation with the CTA obstruction score. Obstructive impairment might have an etiological relationship with vascular involvement. Further investigations could shed new light on the etiology of CTEPH.

Pulmonary hypertension (PH) is a life-threatening disorder, which originates from various aetiologies. Ventilation-perfusion (V/Q) scanning is commonly used to evaluate the differential diagnosis of PH. Meanwhile, previous studies have shown that single-photon emission computed tomography (SPECT)/CT imaging can provide a more detailed analysis for the assessment of pulmonary blood flow. However, there is insufficient evidence supporting the merits of V/Q SPECT/CT image data in detecting pulmonary vascular disease. Here, we report a case of pulmonary arterial hypertension with localized accumulation and peculiar distribution just below the pleura on V/Q SPECT/CT. Our finding is unique, and it suggests that V/Q SPECT/CT image data might be useful to detect blood flow not only in cases of pulmonary embolism, but also in the more commonly encountered PH.

BACKGROUND: The 6th World Symposium on Pulmonary Hypertension (Nice 2018) proposed a new definition of pre-capillary pulmonary hypertension (PH) as a condition with mean pulmonary artery pressure (mPAP) > 20 mmHg, pulmonary artery wedge pressure  ≤ 15 mmHg, and pulmonary vascular resistance (PVR) ≥ 3 Wood units (WU). The characteristics and prognosis of patients with pre-capillary PH, according to this new definition, is unclear. Therefore, we determined the characteristics and survival of patients with borderline pre-capillary PH. METHODS: We retrospectively enrolled 683 patients who underwent their first right heart catheterization at Chiba University, Japan. Among them, 489 patients met the pre-capillary PH requirement with mPAP ≥ 25 mmHg (conventional pre-capillary PH group), while 22 patients met the borderline pre-capillary PH criteria (borderline pre-capillary PH group). Additionally, 16 patients with a mean PAP of 20-25 and PVR of 2-3 WU were also examined. RESULTS: The borderline pre-capillary PH group comprised 4.3% of the total patients with pre-capillary PH, and the majority was in Group 3 (40.9%) or 4 (45.5%). The survival of the borderline pre-capillary PH group tended to be better than that of the conventional pre-capillary PH group. The prognosis of Group3 PH was the worst among the patients with borderline precapillary PH. There was no significant difference in survival between the borderline pre-capillary PH group with PVR ≥ 3 WU and that with PVR of 2-3 2WU, although none of the patients in the latter group died due to right heart failure. CONCLUSIONS: This is the first study conducted in a PH center in an Asian country to reveal the characteristics of patients with pre-capillary PH, according to the Nice 2018 definition. They comprised 4.3% of the total population with pre-capillary PH, and the majority of the pre-capillary PH cases were in either Group3 or 4. The prognosis may be affected by the patients' underlying diseases. Further prospective studies are needed to determine whether the new definition, including the PVR cut-off, is beneficial in clinical practice.

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.

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 3.601.60 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 (&gt; 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.

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.

Background and objectiveChronic 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 /V-A ) as a prognostic and pathophysiological marker in CTEPH. MethodsWe 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 /V-A was also investigated. ResultsNinety-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 /V-A than in those with normal values (61.4% vs 90.4%, P=0.017). Decreased preoperative DLCO /V-A 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. ConclusionDecreased DLCO/V-A 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. This is the first study identifying decreased diffusing capacity for carbon monoxide (DLCO)/alveolar ventilation (V-A) (&lt;80%) as an independent poor prognostic factor in medically treated chronic thromboembolic pulmonary hypertension (CTEPH) patients. This study also demonstrated that DLCO/V-A may reflect peripheral microvasculopathy, which is a major cause of poor outcome.

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by occlusion of pulmonary arteries by organized chronic thrombi. Persistent hypoxemia and residual pulmonary hypertension (PH) following successful pulmonary endarterectomy (PEA) are clinically important problems; however, the underlying mechanisms remain unclear. We have previously reported that residual PH is closely related to severe pulmonary vascular remodeling and hypothesize that this arteriopathy might also be involved in impaired gas exchange. The purpose of this study was to evaluate the association between hypoxemia and pulmonary arteriopathy after PEA. Methods and Results Between December 2011 and November 2014, 23 CTEPH patients underwent PEA and lung biopsy. The extent of pulmonary arteriopathy was quantified pathologically in lung biopsy specimens. We then analyzed the relationship between the severity of pulmonary arteriopathy and gas exchange after PEA. We observed that the severity of pulmonary arteriopathy was negatively correlated with postoperative and follow-up PaO2 (postoperative PaO2: r = -0.73, p = 0.0004; follow-up PaO2: r = -0.66, p = 0.001), but not with preoperative PaO2 (r = -0.373, p = 0.08). Multivariate analysis revealed that the obstruction ratio and patient age were determinants of PaO2 one month after PEA (R-2 = 0.651, p = 0.00009). Furthermore, the obstruction ratio and improvement of pulmonary vascular resistance were determinants of PaO2 at follow-up (R-2 = 0.545, p = 0.0002). Severe pulmonary arteriopathy might increase the alveolar-arterial oxygen difference and impair diffusion capacity, resulting in hypoxemia following PEA. Conclusion The severity of pulmonary arteriopathy was closely associated with postoperative and follow-up hypoxemia.

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

Pulmonary vascular endothelial cells could contribute to maintain homeostasis in adult lung vasculature. "Tissue-resident" endothelial progenitor cells (EPCs) play pivotal roles in postnatal vasculogenesis, vascular repair, and tissue regeneration; however, their local pulmonary counterparts remain to be defined. To determine whether prominin-1/CD133 expression can be a marker of tissue-resident vascular EPCs in the pulmonary circulation, we examined the origin and characteristics of prominin-1/CD133-positive (Prom1(+)) PVECs considering cell cycle status, viability, histological distribution, and association with pulmonary vascular remodeling. Prom1(+) PVECs exhibited high steady-state transit through the cell cycle compared with Prom1(-) PVECs and exhibited homeostatic cell division as assessed using the label dilution method and mice expressing green fluorescent protein. In addition, Prom1(+) PVECs showed more marked expression of putative EPC markers and drug resistance genes as well as highly increased activation of aldehyde dehydrogenase compared with Prom1(-) PVECs. Bone marrow reconstitution demonstrated that tissue-resident cells were the source of >98% of Prom1(+) PVECs. Immunofluorescence analyses revealed that Prom1(+) PVECs preferentially resided in the arterial vasculature, including the resistant vessels of the lung. The number of Prom1(+) PVECs was higher in developing postnatal lungs. Sorted Prom1(+) PVECs gave rise to colonies and formed fine vascular networks compared with Prom1(-) PVECs. Moreover, Prom1(+) PVECs increased in the monocrotaline and the Su-5416 + hypoxia experimental models of pulmonary vascular remodeling. Our findings indicated that Prom1(+) PVECs exhibited the phenotype of tissue-resident EPCs. The unique biological characteristics of Prom1(+) PVECs predominantly contribute to neovasculogenesis and maintenance of homeostasis in pulmonary vascular tissues.

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

Background: The postoperative changes in the coagulation-fibrinolysis system and the association between the system and postoperative course of patients with chronic thromboembolic pulmonary hypertension (CTEPH) who have undergone pulmonary endarterectomy (PEA) remain unclear. Methods and Results: Between 1986 and 2013, 117 patients (55.1+/-11.2 years, preoperative mean pulmonary arterial pressure 46.5+/-10.5 mmHg) underwent PEA, and 15 patients died during the perioperative period. We studied the association between the preoperative coagulation-fibrinolysis markers and surgical outcomes of all patients, and the long-term outcomes of the 102 survivors from the date of PEA. We also investigated the postoperative changes in coagulation-fibrinolysis markers and their association with residual pulmonary hypertension (PH) in 20 consecutive patients. Only an elevated factor VIII level was associated with perioperative death. Thrombomodulin and plasminogen values were significantly increased after PEA. Univariate logistic regression analysis revealed that D-dimer positivity at follow-up was a risk factor for residual PH. Patients with both an elevated fibrinogen level (&gt;= 291 mg/dl [median]) and decreased plasminogen activity (&lt;100% [median]) had significantly worse disease-specific survival than the other patients (5-year disease-specific survival: 84.0% vs. 100%, respectively; P=0.0041 [log-rank test]). Conclusions: Preoperatively high fibrinogen and low plasminogen values in patients with CTEPH are associated with poor long-term postoperative outcome. PEA benefited not only the pulmonary hemodynamics but also the coagulation-fibrinolysis system of patients.