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.

Endothelial cells from pulmonary endarterectomy specimens possess a high angiogenic potential and express high levels of hepatocyte growth factor.

BACKGROUND: Impaired angiogenesis is assumed to be an important factor in the development of chronic thromboembolic pulmonary hypertension (CTEPH). However, the role of endothelial cells (ECs) in CTEPH remains unclear. The aim of this study was to investigate the angiogenic potential of ECs from pulmonary endarterectomy (PEA) specimens. METHODS: We isolated ECs from PEA specimens (CTEPH-ECs) and control EC lines from the intact pulmonary arteries of patients with peripheral lung cancers, using a MACS system. These cells were analyzed in vitro including PCR-array analysis, and the PEA specimens were analyzed with immunohistochemistry. Additionally, the serum HGF levels were determined in CTEPH patients. RESULTS: A three-dimensional culture assay revealed that CTEPH-ECs were highly angiogenic. An angiogenesis-focused gene PCR array revealed a high expression of hepatocyte growth factor (HGF) in CTEPH-ECs. The high expression of HGF was also confirmed in the supernatant extracted from PEA specimens. The immunohistochemical analysis showed expression of HGF on the surface of the thrombus vessels. The serum HGF levels in CTEPH patients were higher than those in pulmonary thromboembolism survivors. CONCLUSION: Our study suggests that there are ECs with pro-angiogenetic character and high expression of HGF in PEA specimens. It remains unknown how these results are attributable to the etiology. However, further investigation focused on the HGF pathway may provide novel diagnostic and therapeutic tools for patients with CTEPH.

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.

Heart Rate and Oxygen Saturation Change Patterns During 6-min Walk Test in Subjects With Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: The 6-min walk test (6MWT) is commonly performed to assess functional status in patients with chronic thromboembolic pulmonary hypertension. However, changes in heart rate and oxygen saturation (SpO2 ) patterns during 6MWT in patients with chronic thromboembolic pulmonary hypertension remain unclear. METHODS: Thirty-one subjects with chronic thromboembolic pulmonary hypertension were retrospectively evaluated to examine the relationships between the change in heart rate (Δheart rate), heart rate acceleration time, slope of heart rate acceleration, heart rate recovery during the first minute after 6MWT (HRR1), change in SpO2 (ΔSpO2 ), SpO2 reduction time, and SpO2 recovery time during 6MWT, and the severity of pulmonary hemodynamics assessed by right heart catheterization and echocardiography. RESULTS: Subjects with severe chronic thromboembolic pulmonary hypertension had significantly longer heart rate acceleration time (144.9 ± 63.9 s vs 96.0 ± 42.5 s, P = .033), lower Δheart rate (47.4 ± 16.9 vs 61.8 ± 13.6 beats, P = .02), and lower HRR1 (13.3 ± 9.0 beats vs 27.1 ± 9.2 beats, P < .001) compared to subjects with mild chronic thromboembolic pulmonary hypertension. Subjects with severe chronic thromboembolic pulmonary hypertension also had significantly longer SpO2 reduction time (178.3 ± 70.3 s vs 134.3 ± 58.4 s, P = .03) and SpO2 recovery time (107.6 ± 35.3 s vs 69.8 ± 32.7 s, P = .004) than did subjects with mild chronic thromboembolic pulmonary hypertension. Multivariate linear regression analysis showed only mean pulmonary arterial pressure independently was associated with heart rate acceleration time and slope of heart rate acceleration. CONCLUSIONS: Heart rate and SpO2 change patterns during 6MWT are predominantly associated with pulmonary hemodynamics in subjects with chronic thromboembolic pulmonary hypertension. Evaluating heart rate and SpO2 change patterns during 6MWT may serve as a safe and convenient way to follow the change in pulmonary hemodynamics.

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.

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.

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.

Severe Pulmonary Arteriopathy Is Associated with Persistent Hypoxemia after Pulmonary Endarterectomy in Chronic Thromboembolic Pulmonary Hypertension.

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 (R2 = 0.651, p = 0.00009). Furthermore, the obstruction ratio and improvement of pulmonary vascular resistance were determinants of PaO2 at follow-up (R2 = 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.

Right ventricular sugars and fats in chronic thromboembolic pulmonary hypertension.

BACKGROUND/OBJECTIVES: Several studies have already shown the correlation between the right ventricle (RV) hemodynamic values and either glucose uptake or fatty acid uptake in the RV, respectively. However, there are few studies to compare the RV metabolic alteration before and after treatment for pulmonary hypertension. The aims of this study are to assess right ventricular glucose and fatty acid in chronic thromboembolic pulmonary hypertension (CTEPH) patients before and after pulmonary thromboendarterectomy and to examine whether there is a correlation between right ventricular glucose and fatty acid uptake. METHODS: To assess glucose and fatty acid accumulation in the RV, [(18)F] fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) and (123)I-ß-methyl iodophenyl pentadecanoic acid (BMIPP) imaging were performed in CTEPH patients before (FDG: n=20, BMIPP: n=13) and after (FDG: n=12, BMIPP: n=8) thromboendarterectomy. RESULTS: Both [(18)F] FDG uptake and (123)I-BMIPP uptake in RV of post-PEA patients obviously decreased after this operation procedure (p<0.01). The right ventricle [(18)F] FDG uptake was also significantly correlated with (123)I-BMIPP uptake (r=0.45, p=0.04). CONCLUSIONS: In this study, we observed that both glucose and fatty acid accumulated in the RV of patients with CTEPH. Although the exact details of the altered energy metabolism in the stressed RV remain unknown, this is the first study to evaluate both glucose and fatty acid uptake before and after thromboendarterectomy in patients with CTEPH, even though the number of the patient is limited.

Pulmonary haemodynamics are correlated with intimal lesions in a rat model of severe PAH: attenuation of pulmonary vascular remodelling with ambrisentan.

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by obstructive lesions and vasoconstriction of the pulmonary arteries. Early therapeutic interventions with vasodilator drugs are thought to be beneficial in PAH. However, it remains unknown whether the severity of intimal obstruction is associated with increased pulmonary arterial pressure and whether reduction of vasoconstriction in the earlier stage by these drugs has a beneficial effect. Therefore, the aims of this study were to investigate these issues in a rat model of severe PAH. Methods A rat model of severe PAH was created by injection of a vascular endothelial growth factor receptor blocker in combination with hypoxia for the first 3 weeks followed by normoxia for the next 9 weeks. To assess intimal obstruction, "the pulmonary artery occlusion index (PAOI)" was developed to digitize all lesions. The small pulmonary arteries were assessed by this index, and the association between right ventricular systolic pressure (RVSP) and PAOI was investigated. An endothelin receptor antagonist, ambrisentan, was administered by gavage to rats during either hypoxia (Prevention study group, n=25) or normoxia (Early treatment group, n=15). RESULTS: PAOI showed a positive correlation with RVSP, and both RVSP and PAOI increased gradually over time. There were no severe occlusive lesions in either group, but the density of partially occlusive lesions was significantly decreased in the Prevention study group. CONCLUSION: A novel PAOI index was developed, and this index was strongly correlated with RVSP. Furthermore, ambrisentan reduced luminal occlusive lesions more effectively when treatment was given during the first 2 weeks of hypoxia.

Coagulation-Fibrinolysis System and Postoperative Outcomes of Patients With Chronic Thromboembolic Pulmonary Hypertension.

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 (≥291 mg/dl [median]) and decreased plasminogen activity (<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.

Importance of carefully interpreting computed tomography images to detect partial anomalous pulmonary venous return.

BACKGROUND: Partial anomalous pulmonary venous return (PAPVR) is characterized by an abnormal connection of the pulmonary vein (PV). The left-to-right shunt results in an increased pulmonary blood flow, which may be followed by developing pulmonary hypertension (PH). We found that computed tomography (CT) scans may be misinterpreted, potentially leaving anomalous PVs undetected when reviewing diagnostic findings of PAPVR patients. The purpose of this study was to delineate this risk and assess the usefulness of our interpretation methods. METHODS: We retrospectively reviewed the records of 8 patients diagnosed with PAPVR, diagnosed with right heart catheterization (RHC) findings, at our department between 1991 and 2013. Our CT screening method for assessing anomalous PVs consisted of two points: 1) confirming that four PVs were connected to the left atrium (LA) and 2) checking that the vena cava was not connected with anomalous PVs. The accuracy of this method was analyzed in a blinded manner. RESULTS: In 4 patients, anomalous PVs delineated on enhanced CT scan images obtained before RHC were undetected. The sensitivity and specificity of detecting PAPVRs using our protocol were 0.800 and 0.978, respectively. Four of 8 patients went on to develop PH. Age at the time of diagnosis was positively correlated with mean pulmonary arterial pressure (r=0.929, p=0.002). CONCLUSION: There is a potential risk of CT scan misinterpretation when looking for anomalous PVs. Careful interpretation of CT findings that focus on PVs may be useful for detecting PAPVR and obtaining a PH differential diagnosis.

Synergistic Effects of ACE Insertion/Deletion and GNB3 C825T Polymorphisms on the Efficacy of PDE-5 Inhibitor in Patients with Pulmonary Hypertension.

BACKGROUND: The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the C825T polymorphism in the G-protein ß3 subunit gene (GNB3) are associated with the efficacy of phosphodiesterase-5 inhibitor (PDE-5I) in erectile dysfunction. In addition, GNB3 genotypes could be associated with clinical worsening in pulmonary hypertension (PH) treated with PDE-5I. However, no studies have described the synergistic effects of gene polymorphisms on drug efficacy in patients with PH. OBJECTIVES: We aimed to examine the effects of combined ACE/GNB3 polymorphisms on the efficacy of PDE-5I in patients with PH. METHODS: This was a retrospective uncontrolled study. Ninety patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH) were treated with PDE-5I. Freedom from clinical worsening and pre- and post-treatment parameters, including the 6-min walk distance (6MWD) and serum brain natriuretic peptide (BNP) levels, were compared between patients with ACE/GNB3 II/TT and non-II/TT genotypes. RESULTS: Time to clinical worsening was significantly longer in patients with the II/TT genotype than in those with the non-II/TT genotype (5-year freedom from clinical worsening: 100 vs. 48.8%, respectively; p = 0.018), even in patients with CTEPH alone. Post-treatment 6MWD and BNP levels in patients with the II/TT genotype tended to be better than those in patients with the non-II/TT genotype. The ACE/GNB3 genotype was a significant predictor of clinical worsening, even after adjusting for pulmonary vascular resistance and 6MWD. CONCLUSIONS: ACE and GNB3 polymorphisms may synergistically influence the efficacy of PDE-5I in patients with PH.

Effects of Surgical and Medical Treatment on Quality of Life for Patients With Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: This study aimed to investigate the predictors of quality of life (QOL) in patients with chronic thromboembolic pulmonary hypertension (CTEPH), changes in QOL after surgical and medical treatments, and the relationship between baseline QOL and survival. METHODS AND RESULTS: QOL was measured in 128 patients with CTEPH (male/female: 42/86, age: 56±12 years, surgical/medical: 65/63) using the Short-Form 36 (SF-36) questionnaire. Multiple regression analysis showed pulmonary vascular resistance (PVR) and 6-min walking distance (6MWD) were associated with physical functioning (PF) (P<0.01) and physical component summary (PCS) (P<0.01). In the surgical group, 7 subscales and 2 summary scores improved significantly, and in the medical group 6 subscales and the mental component summary, although the change in QOL was greater in the surgical group. The patients in the conventional therapy group with higher PF had significantly better survival than those with lower PF (5-years survival: 89.5% vs. 50.8%, P=0.002). This difference in survival was not observed in the group receiving pulmonary arterial hypertension (PAH)-specific therapy (100% vs. 100%, P=0.746). CONCLUSIONS: PVR and 6MWD were associated with PF or PCS in CTEPH patients. QOL improved after surgical or medical therapy, with a greater change in the surgical group. PAH-specific therapy improved survival in patients with lower PF at diagnosis.

Correction: Evaluation of the Microcirculation in Chronic Thromboembolic Pulmonary Hypertension Patients: The Impact of Pulmonary Arterial Remodeling on Postoperative and Follow-Up Pulmonary Arterial Pressure and Vascular Resistance.

[This corrects the article DOI: 10.1371/journal.pone.0133167.].

Evaluation of the Microcirculation in Chronic Thromboembolic Pulmonary Hypertension Patients: The Impact of Pulmonary Arterial Remodeling on Postoperative and Follow-Up Pulmonary Arterial Pressure and Vascular Resistance.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is generally recognized to be caused by persistent organized thrombi that occlude the pulmonary arteries. The aim of this study was to investigate the characteristics of small vessel remodeling and its impact on the hemodynamics in CTEPH patients. METHODS AND RESULTS: Hemodynamic data were obtained from right heart catheterization in 17 CTEPH patients before pulmonary endarterectomy (PEA). Lung tissue specimens were obtained at the time of PEA. Pathological observations and evaluation of quantitative changes in pulmonary muscular arteries and veins were performed using light microscopy on 423 slides in 17 patients. The relationship between the results and the hemodynamics of CTEPH was investigated. Pulmonary arteriopathy and venopathy were recognized in most cases, although no plexiform lesions and no capillary-hemangiomatosis-like lesions were detected in any of the specimens. The severity of pulmonary arteriopathy was correlated with pulmonary vascular resistance (PVR) in the postoperative and follow-up periods. The PVR and mean pulmonary arterial pressure were significantly higher in the high-obstruction group than in the low-obstruction group. The findings in pulmonary venopathy were similar to the findings seen in pulmonary veno-occlusive disease in some cases, although severe venopathy was only observed in a portion of the pulmonary veins. There was a significant correlation between the extent of pulmonary arteriopathy and venopathy, although an effect of pulmonary venopathy to hemodynamics, including pulmonary arterial wedged pressure (PAWP), could not be identified. CONCLUSION: The vascular remodeling of the pulmonary muscular arteries was closely associated with the hemodynamics of CTEPH. Severe pulmonary arteriopathy might be related to residual pulmonary hypertension after PEA. Those altered pulmonary arteries might be a new target for the persistent PH after the operation.

Pentraxin3 in chronic thromboembolic pulmonary hypertension: a new biomarker for screening from remitted pulmonary thromboembolism.

BACKGROUND: Pentraxin3 (PTX3) is a protein, which has multifaceted effects on innate immunity, angiogenesis, and vascular remodeling then could be a disease marker of acute myocardial infarction, heart failure, vasculitis. In addition, PTX3 has been recognized as a biomarker for pulmonary arterial hypertension, however whether it is the case in chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. Therefore, we investigated whether PTX3 would be a useful biomarker for detecting CTEPH with respect to differentiation from stable pulmonary thromboembolism (PTE), in comparison to other biomarkers. METHODS: Plasma PTX3 and brain natriuretic peptide (BNP) levels were measured in 70 patients with CTEPH at their first diagnostic right heart catheterization (CTEPH group) and in 20 patients with clinically stable PTE more than three months after the acute episode (control group). The levels of plasma C-reactive protein (CRP) and heart-type fatty acid-binding protein (H-FABP) were also analyzed to compare the diagnostic ability of these biomarkers. RESULTS: The mean level of PTX3 (ng/mL) was significantly higher in the CTEPH group than in the control group (5.51±4.53 versus 2.01±0.96, respectively), and PTX3 levels had mild negative correlation with cardiac output. BNP levels were also higher in the CTEPH group and better correlated with pulmonary hemodynamics than PTX3. However, a receiver operating characteristic (ROC) curve showed PTX3 levels were better for detecting CTEPH, and could detect CTEPH patients with less severe pulmonary hemodynamics and low plasma BNP levels. There was no significant increase in CRP and H-FABP levels in the CTEPH patients. CONCLUSIONS: Plasma PTX3 level was the most sensitive biomarker of CTEPH. Although plasma PTX3 levels did not correlate with the severity of the pulmonary hemodynamics compared to BNP, high levels in clinically stable patients following PTE should prompt a further work-up for CTEPH, which may lead to an early diagnosis.