Ayako Shigeta

Role of 320-Slice CT Imaging in the Diagnostic Workup of Patients With Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND Right-sided heart catheterization (RHC) and pulmonary digital subtraction angiography (PDSA) are the standard methods used in diagnosing suspected or defi nite chronic thromboembolic pulmonary hypertension (CTEPH). We studied the ability of 320-slice CT imaging to detect simultaneously chronic thromboembolic fi ndings in the pulmonary arteries and pulmonary hemodynamics based on the curvature of the interventricular septum (IVS) in CTEPH . METHODS Forty-four patients with high clinical suspicion of CTEPH underwent RHC, PDSA, and enhanced double-volume retrospective ECG-gated 320-slice CT scan. We measured the sensitivity and specificity of CT imaging to detect thrombi in the pulmonary arteries compared with PDSA. We also compared IVS bowing (expressed as curvature) measured on the short-axis cine heart image with pulmonary arterial pressure (PAP) obtained by RHC. RESULTS Compared with PDSA, the sensitivity and specificity of CT imaging to detect chronic thromboembolic findings were 97.0% and 97.1% at the main/lobar level and 85.8% and 94.6% at the segmental level, respectively. The correlation coefficients of IVS curvature with systolic PAP and mean PAP were 2 0.79 ( P , .001) and 2 0.86 ( P , .001), respectively. CONCLUSIONS The use of 320-slice CT imaging allows for less invasive and simultaneous detection of thrombi and evaluation of pulmonary hemodynamics for the diagnostic work-up of CTEPH.

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. METHODSANDRESULTS 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.

Home-based pulmonary rehabilitation in patients with inoperable or residual chronic thromboembolic pulmonary hypertension: A preliminary study

BACKGROUND Management of chronic thromboembolic pulmonary hypertension (CTEPH) has recently improved because of advances in pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and disease-targeted medications. However, patients with inoperable CTEPH or persistent pulmonary hypertension (PH) after these interventions continue to exhibit impaired exercise capacity and limited quality of life (QOL). METHODS Eight patients with inoperable or residual CTEPH (mean age, 64±12 years; WHO functional class II/III, 6/2; mean pulmonary artery pressure, 47±13 mmHg) in stable condition and receiving disease-targeted medications participated in a 12-week home-based pulmonary rehabilitation program (muscle strength training, respiratory exercises, and walking) with supervised hospital sessions from March 2012 to January 2014. Efficacy parameters were prospectively evaluated at baseline and at completion of the 12-week program. RESULTS After completion of the pulmonary rehabilitation program, the 6-minute walking distance (6MWD) (33.3±25.1 m), St. George׳s Respiratory Questionnaire activity score, quadriceps force, and 7-day physical activity level were significantly improved compared with baseline. All subjects completed the rehabilitation program. Although one patient experienced presyncope during the in-hospital exercise sessions, no other severe adverse events or complications of pulmonary rehabilitation were observed. CONCLUSIONS These findings suggest that home-based pulmonary rehabilitation with closely supervised sessions may safely improve exercise capacity, leg muscle strength, general activity in daily life and health-related QOL in CTEPH patients.

CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema

Excessive apoptosis and prolonged inflammation of alveolar cells are associated with the pathogenesis of pulmonary emphysema. We aimed to determine whether CD40 affects alveolar epithelial cells and endothelial cells, with regard to evoking apoptosis and inflammation. Mice were repeatedly treated with agonistic-anti CD40 antibody (Ab), with or without agonistic-anti Fas Ab, and evaluated for apoptosis and inflammation in lungs. Human pulmonary microvascular endothelial cells and alveolar epithelial cells were treated with agonistic anti-CD40 Ab and/or anti-Fas Ab to see their direct effect on apoptosis and secretion of proinflammatory molecules in vitro. Furthermore, plasma soluble CD40 ligand (sCD40L) level was evaluated in patients with chronic obstructive pulmonary disease (COPD). In mice, inhaling agonistic anti-CD40 Ab induced moderate alveolar enlargement. CD40 stimulation, in combination with anti-Fas Ab, induced significant emphysematous changes and increased alveolar cell apoptosis. CD40 stimulation also enhanced IFN-γ-mediated emphysematous changes, not via apoptosis induction, but via inflammation with lymphocyte accumulation. In vitro, Fas-mediated apoptosis was enhanced by CD40 stimulation and IFN-γ in endothelial cells and by CD40 stimulation in epithelial cells. CD40 stimulation induced secretion of CCR5 ligands in endothelial cells, enhanced with IFN-γ. Plasma sCD40L levels were significantly increased in patients with COPD, inversely correlating to the percentage of forced expiratory volume in 1 s and positively correlating to low attenuation area score by CT scan, regardless of smoking history. Collectively CD40 plays a contributing role in the development of pulmonary emphysema by sensitizing Fas-mediated apoptosis in alveolar cells and increasing the secretion of proinflammatory chemokines.

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.

Electrocardiogram-gated 320-slice multidetector computed tomography for the measurement of pulmonary arterial distensibility in chronic thromboembolic pulmonary hypertension.

Background We aimed to study whether pulmonary arterial distensibility (PAD) correlates with hemodynamic parameters in chronic thromboembolic pulmonary hypertension (CTEPH) using electrocardiogram (ECG)-gated 320-slice multidetector computed tomography (MDCT). Methods and Findings ECG-gated 320-slice MDCT and right heart catheterization (RHC) was performed in 53 subjects (60.6±11.4 years old; 37 females) with CTEPH. We retrospectively measured the minimum and maximum values of the cross sectional area (CSA) of the main pulmonary artery (mainPA), right pulmonary artery (rtPA), and left pulmonary artery (ltPA) during one heartbeat. PAD was calculated using the following formula: PAD = [(CSAmaximum−CSAminimum)/CSAmaximum]×100(%). The correlation between hemodynamic parameters and PAD was assessed. Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were 40.8±8.7 mmHg and 8.3±3.0 wood units, respectively. PAD values were as follows: mainPA (14.0±5.0%), rtPA (12.8±5.6%), and ltPA (9.7±4.6%). Good correlations existed between mainPAD, with mPAP (r = −0.594, p<0.001) and PVR (r = −0.659, p<0.001). The correlation coefficients between rtPAD and ltPAD with pulmonary hemodynamics were all lower or equal than for mainPAD. Conclusions PAD measured using ECG-gated 320-slice MDCT correlates with pulmonary hemodynamics in subjects with CTEPH. The mainPA is suitable for PAD measurement.

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

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.

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.

Association of deep vein thrombosis type with clinical phenotype of chronic thromboembolic pulmonary hypertension.

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) has been considered to be caused by single or recurrent pulmonary embolism (PE) arising from deep vein thrombosis (DVT). In Japan, female predominance and association of HLA-B*5201 with CTEPH unrelated to DVT were reported. In acute PE residual proximal DVT is associated with larger obstruction of pulmonary arteries. However, it remains uncertain whether DVT and the type of DVT are associated with clinical phenotype of CTEPH. PURPOSE To clarify the association of DVT and DVT type with clinical phenotype of CTEPH. METHODS Among 98 consecutive patients who underwent 16 or 64-slice multidetector CT angiography and indirect venography, 91 patients (66% female, age: 56±3 years) with adequate images were enrolled. The associations of DVT and DVT type with pulmonary hemodynamics, CT obstruction index and other clinical parameters were analyzed. RESULTS DVT was found in 45 patients (49.5%) (distal: 12, proximal: 33), and was significantly associated with male gender and recurrent type. Furthermore, it was more frequent in HLA-B*5201-negative, and d-dimer positive patients. Compared with distal DVT, proximal DVT was associated with male gender, larger CT obstruction index (48.6±13.0 vs. 34.1±13.2%, p=0.004), and higher mean pulmonary arterial pressure (48.2±12.8 vs. 40.8±7.9 mmHg, p=0.03). Proximal DVT was significantly associated with the central type of CTEPH only in HLA-B*5201-negative patients. CONCLUSIONS The existence and type of DVT were associated with clinical phenotype of CTEPH, and proximal DVT might contribute to the central type of CTEPH in only HLA-B*5201-negative patients.