Clinical usefulness of endothelial progenitor cells in predicting the efficacy of riociguat in chronic thromboembolic pulmonary hypertension.

Endothelial dysfunction is important in the pathology of pulmonary hypertension, and circulating endothelial progenitor cells (EPCs) have been studied to evaluate endothelial dysfunction. In patients with chronic thromboembolic pulmonary hypertension (CTEPH), riociguat reportedly increases the number of circulating EPCs. However, the relationship between EPC numbers at baseline and changes in clinical parameters after riociguat administration has not been fully elucidated. Here, we evaluated 27 treatment-naïve patients with CTEPH and analyzed the relationships between EPC number at diagnosis and clinical variables (age, hemodynamics, atrial blood gas parameters, brain natriuretic peptide, and exercise tolerance) before and after riociguat initiation. EPCs were defined as CD45dim CD34+ CD133+ cells and measured by flow cytometry. A low number of circulating EPCs at diagnosis was significantly correlated with increased reductions in mean pulmonary arterial pressure (mPAP) (correlation coefficient = 0.535, P = 0.004) and right atrial pressure (correlation coefficient = 0.618, P = 0.001) upon riociguat treatment. We then divided the study population into two groups according to the mPAP change: a weak-response group (a decrease in mPAP of 4 mmHg or less) and a strong-response group (a decrease in mPAP of more than 4 mmHg). The number of EPCs at diagnosis was significantly lower in the strong-response group than in the weak-response group (P = 0.022), but there were no significant differences in other clinical variables or in medication profiles. In conclusion, circulating EPC numbers could be a potential predictor of the therapeutic effect of riociguat in CTEPH patients.

＜Editors' Choice＞ Differential effects of combination therapy on the components of the risk stratification table in patients with idiopathic or heritable pulmonary arterial hypertension in a Japanese population.

Risk stratification by ESC/ERS guideline is recommended to estimate the vital prognosis and select the treatment strategy in patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH). However, we are not confident whether we can achieve low-risk status in the risk table at the follow-up shortly after combination therapy. Therefore, we aimed to verify the effects of combination therapy in IPAH/HPAH on each category of the risk table at diagnosis and at the first follow-up. We retrospectively analyzed 10 consecutive patients with IPAH/HPAH with no previous treatment history diagnosed at Nagoya University Hospital between October 2014 and January 2019. Four categories including symptoms, exercise tolerance, BNP levels and hemodynamics were validated both at baseline and at the first follow-up of right heart catheterization. Score of 1, 2 and 3 were assigned to the low risk, intermediate risk and high risk, respectively. In each category the highest score was adopted. The scores at diagnosis were compared with those at the first follow-up. The result shows that all patients were female, median age was 32 years old, and were treated with initial combination therapy. The median total risk score also was improved from 2.6 to 1.4 (p<0.01). However, the score in exercise tolerance was not improved (3 to 2.5 p=0.16). In conclusion, at the first follow up shortly after the initial combination therapy of IPAH/HPAH, the mean total risk score was significantly improved, however, even patients in the low-risk status may not achieve improvement in exercise tolerance.

Mortality, Recurrent Thromboembolism and Major Bleeding in Cancer-Associated and Non-Cancer Pulmonary Embolism Patients Treated With Direct Oral Anticoagulants.

BACKGROUND: Pulmonary embolism (PE) is a potentially fatal form of venous thromboembolism (VTE). This study compares the mortality, incidence of recurrent VTE, and incidence of major bleeding between non-cancer and cancer-associated PE patients treated with direct oral anticoagulants (DOACs).Methods and Results:This was a retrospective, observational, single-center study involving 130 consecutive patients (87 with active cancer; 43 without cancer) who received DOAC treatment for PE between January 2016 and December 2019. Kaplan-Meier analysis showed significantly higher mortality in cancer-associated PE patients than in non-cancer patients (35/87 [40%] vs. 1/43 [2%], P<0.001, log-rank test, HR 18.6 [95% CI: 2.5-136.0]). In contrast, the cumulative incidences of recurrent VTE and major bleeding were comparable between the 2 groups. Among the cancer-associated PE patients, the incidence for the composite outcome of recurrent VTE or major bleeding was significantly higher in patients undergoing chemotherapy than in those not undergoing chemotherapy (9/37 [24%] vs. 2/50 [4%], P=0.004, log-rank test, HR 6.9 [95% CI: 1.5-32.0]). CONCLUSIONS: Although cancer-associated PE patients treated with DOACs showed higher mortality compared with non-cancer patients, presumably because of the presence of cancer, the risk of recurrent VTE or major bleeding was comparable between the 2 groups. Thus, DOAC is an important treatment option for cancer-associated PE, although underlying cancer-related risks (e.g., chemotherapy) remain.

Endostatin and Vascular Endothelial Growth Factor-A165b May Contribute to Classification of Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is characterized by dysregulation of small pulmonary arteries. In addition to endostatin (ES), placenta growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), and the anti-angiogenesis isoform of VEGF-A (VEGF-A165b) are associated with PH. However, the usefulness of these biomarkers in PH in unknown. We investigated whether these 4 biomarkers are related to PH classification. Methods and Results: Between July 2015 and August 2017, 33 control patients and 107 PH patients were enrolled in the study. Among the PH patients, 48 had pulmonary arterial hypertension (PAH), 5 had left heart disease-associated PH (LHD-PH), 4 had lung disease-associated PH (LD-PH), and 50 had chronic thromboembolic PH (CTEPH). Among the PAH patients, 16 had idiopathic PAH (IPAH) and 17 had connective tissue disease-associated PAH (CTD-PAH). PlGF, total VEGF-A, and VEGF-A165b levels were measured in the control and PH groups. ES was only measured in the PH group. VEGF-A165b levels were significantly higher in the LD-PH group than in the PAH, LHD-PH, and CTEPH groups (all P<0.001). PlGF levels were significantly higher in the CTD-PAH group than in the IPAH and control groups. ES levels were significantly correlated with the 6-min walk distance (P<0.001), B-type natriuretic peptide (P<0.001), and pulmonary vascular resistance (P=0.008). Conclusions: ES could detect CTD-PAH in PAH and may be an indicator of PH severity. VEGF-A165b was useful in detecting LD-PH.

Single-center prognostic validation of the risk assessment of the 2015 ESC/ERS guidelines in patients with pulmonary arterial hypertension in Japan.

The 2015 European Society of Cardiology/European Respiratory Society guidelines for the diagnosis and treatment of pulmonary hypertension include a multidimensional risk assessment for patients with pulmonary arterial hypertension (PAH). However, prognostic validations of this risk assessment are limited, especially outside Europe. Here, we validated the risk assessment strategy in PAH patients in our institution in Japan. Eighty consecutive PAH patients who underwent right heart catheterization between November 2006 and December 2018 were analyzed. Patients were classified as low, intermediate, or high risk by using a simplified version of the risk assessment that included seven variables: World Health Organization functional class, 6-min walking distance, peak oxygen consumption, brain natriuretic peptide, right atrial pressure, mixed venous oxygen saturation, and cardiac index. The high-risk group showed significantly higher mortality than the low- or intermediate-risk group at baseline (P < 0.001 for both comparisons), and the mortalities in the intermediate- and low-risk groups were both low (P = 0.989). At follow-up, patients who improved to or maintained a low-risk status showed better survival than those who did not (P = 0.041). Our data suggest that this risk assessment can predict higher mortality risk and long-term survival in PAH patients in Japan.

Addition of a bilateral access form of peripheral extracorporeal membrane oxygenation rescued a patient with idiopathic pulmonary arterial hypertension who developed circulatory collapse immediately after childbirth.

Pregnancy is not advised for patients with Pulmonary hypertension (PH) because of high risk of PH crisis. However, some patients have undiagnosed idiopathic pulmonary arterial hypertension (IPAH) before pregnancy. Upfront combination therapy has high efficacy for patients with IPAH. However, some patients are unable to stand until upfront combination therapy has worked sufficiently. The extracorporeal membrane oxygenation (ECMO) system has been proposed as a bridging therapy to recovery for patients with IPAH. Here, we report a case where a novel form of peripheral ECMO assist plus upfront combination therapy containing intravenous epoprostenol rescued a female patient diagnosed with IPAH just after childbirth. Following this treatment, the patient could successfully transition from intravenous epoprostenol to oral selexipag.

Medium-term health-related quality of life in patients with pulmonary arterial hypertension treated with goal-oriented sequential combination therapy based on exercise capacity.

BACKGROUND: Pulmonary arterial hypertension (PAH) remains a life-threatening condition, despite modern therapies. We prospectively investigated the therapeutic health-related quality of life (HRQOL) effects of goal-oriented sequential combination therapy based on exercise capacity in patients newly diagnosed with PAH. METHODS: To examine the changes in HRQOL in PAH patients, we treated 30 patients newly diagnosed with PAH with goal-oriented sequential combination therapy based on exercise capacity. We monitored exercise capacity by cardiopulmonary exercise testing and observed the benefit of using a peak VO2 cut-off of 15 mL/kg/min to guide combination therapy. First-line treatment was an endothelin receptor antagonist (ERA); second-line treatment was the addition of a phosphodiesterase-5 inhibitor (PDE-5I). At baseline and at 3, 6, and 12 months, HRQOL was evaluated by using the eight-item Medical Outcomes Survey Short Form Health Survey. RESULTS: At 12 months, 100% of PAH patients were receiving an ERA, and 82% an ERA + PDE-5I. The mean physical component summary (PCS) score was 33.5 at baseline, 41.2 at 3 months, 40.8 at 6 months, and 42.0 at 12 months, and the mean mental component summary (MCS) scores were 45.6, 47.0, 50.0, and 50.1, respectively. PCS score was significantly greater at 3 months than at baseline (P = 0.035). MCS score was comparable at 3 months and at baseline, but was significantly greater at 6 and 12 months than at baseline (P = 0.033, P = 0.028, respectively). Thus, PCS score improved soon after initiation of therapy, and MCS score improved later. CONCLUSIONS: Together, these results suggest that goal-oriented sequential combination therapy based on exercise capacity improves HRQOL in patients with PAH.

Goal-Oriented Sequential Combination Therapy Evaluated Using Cardiopulmonary Exercise Parameters for the Treatment of Newly Diagnosed Pulmonary Arterial Hypertension　- Goal-Oriented Therapy Evaluated by Cardiopulmonary Exercise Testing for Pulmonary Arterial Hypertension (GOOD EYE).

Background: Many treatment options are available for pulmonary arterial hypertension (PAH), but specific recommendations for long-term treatment are unavailable. We compared prognosis in PAH patients receiving goal-oriented, sequential combination therapy evaluated using cardiopulmonary exercise testing (CPX) parameters or conventional empiric therapy. Methods and Results: The Goal-Oriented Therapy Evaluated by Cardiopulmonary Exercise Testing for Pulmonary Arterial Hypertension (GOOD EYE) study was a multicenter, retrospective/prospective study in which a total of 129 patients with newly diagnosed PAH were enrolled (goal-oriented sequential combination therapy, n=42; conventional empiric therapy, n=87). Patients in the goal-oriented therapy group received sequential combination therapy, the efficacy of which was regularly evaluated using CPX parameters. Patients in the conventional empiric therapy group received conventional empiric therapy. The primary endpoint was cardiovascular death. In the goal-oriented therapy group, plasma brain natriuretic peptide, mean pulmonary arterial pressure, pulmonary vascular resistance, and 6-min walk test were significantly improved at 12 months compared with baseline. Survival in the goal-oriented therapy group at 1, 2, and 3 years (97.6%, 95.2%, and 86.0%, respectively) tended to be higher than that in the conventional empiric therapy group (P=0.082). Conclusions: Goal-oriented sequential combination therapy evaluated using CPX parameters may be associated with a favorable prognosis compared with conventional empiric therapy in patients with newly diagnosed PAH.

Usefulness of scoring right ventricular function for assessment of prognostic factors in patients with chronic thromboembolic pulmonary hypertension.

Right ventricular (RV) function is associated with prognosis in chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to establish an RV dysfunction score using RV echocardiographic parameters to clarify the clinical characteristics in patients with CTEPH and to compare RV dysfunction score with parameters such as World Health Organization (WHO) functional class, hemodynamics, exercise capacity, and plasma BNP level. We enrolled 35 inpatients with CTEPH (mean age, 62 ± 15 years, 15 males). We constructed 'an RV dysfunction score' calculated as the summation of each point awarded for the presence of four parameters: tricuspid annular plane systolic excursion (TAPSE) < 16 mm, 1 point; tissue Doppler-derived tricuspid lateral annular systolic velocity (S') < 10 cm/s, 1 point; right ventricular fractional area change (RVFAC) < 35%, 1 point; and right ventricular myocardial performance index (RV-MPI) > 0.4, 1 point. TAPSE, S', RVFAC, and RV-MPI was 18.7 ± 4.8 mm, 11.9 ± 3.1 cm/s, 33.5 ± 13.9%, and 0.39 ± 0.2, respectively. The RV dysfunction score was associated with symptom [WHO functional class (p = 0.026)], hemodynamics [mean PAP (p = 0.01), cardiac index (p = 0.009), pulmonary vascular resistance (p = 0.001), and SvO2 (p = 0.039)], exercise capacity [6-min walk distance (p = 0.046), peakVO2 (p = 0.016), and VE/VCO2 slope (p = 0.031)], and plasma BNP level (p = 0.005). This RV dysfunction score using the four RV echocardiographic parameters could be a simple and useful scoring system to evaluate prognostic factors in patients with CTEPH.

Left ventricular end-diastolic dimension and septal e' are predictors of cardiac index at rest, while tricuspid annular plane systolic excursion is a predictor of peak oxygen uptake in patients with pulmonary hypertension.

Little is known regarding a correlation of hemodynamics at rest or exercise capacity with echocardiographic parameters in patients with pulmonary hypertension (PH). To clarify these potential correlations, we performed transthoracic echocardiography, right heart catheterization, and cardiopulmonary exercise testing in 53 patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Left ventricular end-diastolic dimension (LVDd), early diastolic velocity of the septal mitral annulus (septal e'), tricuspid regurgitation peak gradient (TRPG), and tricuspid annular plane systolic excursion (TAPSE) were significantly correlated with cardiac index (LVDd; r = 0.477, P < 0.001, septal e'; r = 0.463, P = 0.001, TRPG; r = - 0.455, P = 0.001 and TAPSE; r = 0.406, P = 0.003, respectively). Multiple regression analysis revealed that LVDd and septal e' were significantly associated with cardiac index (CI) and stroke volume index at rest. Among the exercise capacity markers evaluated, TAPSE, TRPG, and LVDd were significantly correlated with peak oxygen uptake (TAPSE; r = 0.534, P < 0.001, TRPG; r = - 0.466, P = 0.001 and LVDd; r = 0.411, P = 0.002, respectively). Multiple regression analysis showed that TAPSE was significantly associated with peak oxygen uptake (VO2). In PAH and CTEPH patients, LVDd and septal e' were significantly associated with CI at rest, whereas TAPSE was significantly associated with peak VO2. Echocardiographic parameters may predict the prognostic factors of PAH and CTEPH patients.

Circulatory power and ventilatory power over time under goal-oriented sequential combination therapy for pulmonary arterial hypertension.

Many therapeutic options are available for patients with pulmonary arterial hypertension (PAH). However, little is known about the effects of sequential combination therapy on exercise capacity. Here we monitored exercise capacity by cardiopulmonary exercise testing (CPX) and observed the benefit of using a peak VO2 cutoff of 15 mL/kg/min to guide combination therapy. Thirty patients newly diagnosed with PAH were treated with goal-oriented sequential combination therapy. Endothelin receptor antagonists (ERA) were the first-line treatment, with phosphodiesterase type 5 inhibitors (PDE-5i) as the preferred combination partner. The patients underwent cardiac catheterization at baseline and after 12 months and CPX at baseline and after three, six, and 12 months. Circulatory power (CP) was defined as the product of peak O2 uptake and peak systolic blood pressure (SBP); ventilatory power (VP) was defined as peak SBP divided by the minute ventilation-CO2 production slope. After 12 months, ERA had been administered to 100% of the study patients and PDE-5i to 82%. Mean CP at baseline and after three, six, and 12 months was 1807, 2063, 2248, and 2245 mmHg·min/mL/kg, respectively, and mean VP was 2.93, 3.53, 4.16, and 3.68 mmHg, respectively. CP was greater after 6 months than at baseline ( P = 0.047); VP was greater after three months than at baseline ( P = 0.019) and further improved at six months compared with three months ( P = 0.040). Therefore, repeated CPX assessment, including measurement of CP and VP, can provide useful information regarding the efficacy of goal-oriented treatment for PAH.

Effects of bosentan on peripheral endothelial function in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.

Endothelin receptor antagonists (ERAs) have been shown to improve the prognosis of patients with pulmonary arterial hypertension (PAH). However, the effect of the oral dual ERA bosentan on peripheral endothelial dysfunction (PED), as assessed by flow-mediated vasodilation (FMD), in patients with pulmonary hypertension is not well characterized. We investigated the effect of bosentan on PED in patients with PAH or inoperable chronic thromboembolic pulmonary hypertension (CTEPH). A total of 18 patients with PAH and 8 with CTEPH were treated with bosentan. All patients underwent FMD assessment before and after 3 months of bosentan treatment. Whereas FMD increased from 6.01% ± 2.42% at baseline to 8.07% ± 3.18% after 3 months (P < 0.0001) in patients with PAH, those with CTEPH showed no change in FMD after bosentan therapy. In addition, FMD at baseline showed no correlation with pulmonary vascular resistance (r = 0.09) or plasma brain natriuretic peptide levels (r = -0.23) in patients with PAH. Bosentan treatment ameliorated PED in patients with PAH but not in those with inoperable CTEPH. In addition, FMD did not correlate with PAH severity.