Safe and successful transition from oral selexipag to subcutaneous treprostinil in a patient with idiopathic pulmonary arterial hypertension treated with triple combination therapy.

Some patients with pulmonary arterial hypertension (PAH) might undergo transition to parenteral prostacyclin analogs due to inadequate response to oral combination therapy. However, there is no consensus on how transition from oral selexipag to subcutaneous treprostinil should be performed. Herein, we report a 56-year-old woman diagnosed with idiopathic PAH that was treated with initial combination therapy (10 mg of macitentan, 40 mg of tadalafil, and 3.2 mg of selexipag daily). Mean pulmonary arterial pressure (PAP) improved from 63 to 39 mm Hg. Transition to parenteral prostacyclin analog was required because cardiac index was below 2.5 L/min/m2. The selexipag was tapered off while subcutaneous treprostinil was titrated up to 30 ng/kg/min over 19 days. Hemodynamic parameters were slightly better than those before the transition. The mean PAP improved to 32 mm Hg by further gradual increases of subcutaneous treprostinil up to 60 ng/kg/min. Therefore, the patient having idiopathic PAH with inadequate response to oral triple combination therapy experienced successful transition from selexipag to subcutaneous treprostinil. Hemodynamic parameters were slightly more improved at a dose of 30 ng/kg/min of subcutaneous treprostinil than at a dose of 3200 µg daily of selexipag in the midst of disease progression. Learning objectives: There is limited evidence for transition of pulmonary vasodilators, especially from oral selexipag to subcutaneous treprostinil. Detailed change in hemodynamic parameters before and after transition and the way of performing transition in patients with idiopathic pulmonary arterial hypertension with exacerbations despite treatment with oral triple combination therapy may provide useful information for better management in the clinical setting.

Right ventricular pressure overload related to residual thrombotic burden in patients 1 year after acute pulmonary embolism: From the Nagoya PE study.

INTRODUCTION: Residual pulmonary thrombus is an important factor affecting long-term prognosis after acute pulmonary embolism (PE). In this sub-analysis of the Nagoya PE study, we aimed to evaluate the relationship between residual thrombi detected by our refined computed tomography (CT) imaging protocol and the results of a multifaceted assessment of patients 1 year after acute PE. MATERIALS AND METHODS: The Nagoya PE study was a prospective observational study of patients diagnosed with acute PE. At 1 year, patients were evaluated multifacetedly, including by enhanced CT using our refined protocol. RESULTS AND CONCLUSION: Forty-three patients completed full testing at 1 year. Patients were divided into three groups according to the modified CT obstruction index (mCTOI): no pulmonary thrombus, low mCTOI, and high mCTOI. At baseline, left ventricular end-diastolic dimension and tricuspid regurgitation (TR) pressure gradient differed significantly across the three groups. At 1 year, patients with TR velocity > 2.8 m/s were found only in the high mCTOI group (P = .022). No difference was observed in symptoms, exercise tolerance, and quality of life score. Multivariate regression analysis revealed that TR velocity > 2.8 m/s (P = .001) and change in oxygen saturation during a 6-min walking test (P = .043) at 1 year were significantly related to mCTOI at 1 year. High thrombotic burden might be detected in patients with right ventricular pressure overload at diagnosis of acute PE or after 1 year. These patients should be carefully and multifacetedly assessed for potential chronic thromboembolic pulmonary disease or chronic thromboembolic pulmonary hypertension.

Pulmonary tumor thrombotic microangiopathy with thrombus in pulmonary artery caused by diffuse sclerosing variant of thyroid papillary adenocarcinoma: A case report.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal disease associated with malignant tumors that progresses to pulmonary hypertension. Gastric cancer is the most common cause, followed by breast cancer and lung cancer, whereas PTTM due to thyroid cancer has not been reported. In addition to pulmonary obstruction by tumor embolism, tumor cells stimulate endothelial cells to release angiogenetic factors, which induce remodeling of pulmonary arteries and veins and lead to lymphatic obstruction. There is limited information on the relationship between thrombus and PTTM. We herein report an autopsy case with PTTM which was caused by diffuse sclerosing variant of thyroid papillary adenocarcinoma, in which differential diagnosis included the acute phase of chronic thromboembolic pulmonary hypertension.

Usefulness of a refined computed tomography imaging method to assess the prevalence of residual pulmonary thrombi in patients 1 year after acute pulmonary embolism: The Nagoya PE study.

BACKGROUND: Post-pulmonary embolism (PE) syndrome is an important clinical condition that can affect the long-term prognosis after acute PE. OBJECTIVE: We aimed to evaluate the prevalence of residual pulmonary thrombi and the thrombotic burden 1 year after acute PE, by using our refined computed tomography (CT) imaging method. PATIENTS/METHODS: In this prospective study, patients diagnosed with acute PE were recruited and examinations were conducted at 1 month, 6 months, and 1 year. Especially at 1 year, patients were evaluated multifacetedly, including by laboratory tests, quality-of-life, 6-min walking test, and enhanced CT. RESULTS: Fifty-two patients were enrolled. Two patients (3.8%) developed chronic thromboembolic pulmonary hypertension. A total of 43 patients completed evaluation at 1 year, among whom (74%) had residual thrombi, with a median modified CT obstruction index (mCTOI) of 10.7%. In multivariate analysis, residual thrombi at 1 month was the only factor significantly related to residual thrombi at 1 year (odds ratio, 103.4; 95% confidence interval, 4.2-2542.1). The tricuspid regurgitation pressure gradient ≥60 mmHg and left ventricular end-diastolic dimension at diagnosis were significantly related to mCTOI at 1 year (ß = 0.367, P = .003; and ß = -0.435, P = .001, respectively). CONCLUSIONS: Using our improved CT imaging protocol, we found a high prevalence of residual thrombi 1 year after acute PE. Furthermore, right ventricular overload was related to the thrombotic burden. The long-term treatment strategy of acute PE could be modified to include precise CT imaging.

＜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.

Left Upper Lobe Trisegmentectomy After Pulmonary Endarterectomy.

Major pulmonary resection has been successfully performed after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension in a few cases. A pulmonary nodule was detected in a 68-year-old man with a diagnosis of chronic thromboembolic pulmonary hypertension. After pulmonary hypertension was resolved with pulmonary endarterectomy, left upper lobe trisegmentectomy was performed for small lung cancer. Dissection of the pulmonary artery was carefully performed with a possibility of a fragile state on the arterial wall due to previous pulmonary endarterectomy. Pathologically, the arterial media with an uneven thickness was exposed to the vascular lumen in the resected pulmonary artery.

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.

Assessment of Severity in Chronic Thromboembolic Pulmonary Hypertension by Quantitative Parameters of Dual-Energy Computed Tomography.

OBJECTIVE: The objective of this study was to assess the correlation between dual-energy computed tomography quantitative parameters and hemodynamics in patients with chronic thromboembolic pulmonary hypertension. METHODS: Dual-energy computed tomography of 52 chronic thromboembolic pulmonary hypertension patients were evaluated retrospectively. The mean lung perfused blood volume (lung PBV) and the mean pulmonary artery (PA) enhancement measured at pulmonary parenchymal phase were compared with the hemodynamics by Spearman rank correlation coefficient (rs) and receiver operating characteristic analysis. RESULTS: Lung PBV was correlated with mean pulmonary arterial pressure (rs = 0.47, P < 0.001). Pulmonary artery enhancement was correlated with cardiac index (rs = -0.49, P < 0.001) and pulmonary vascular resistance (rs = 0.48, P < 0.001). The areas under the curves were 0.86 for lung PBV to predict mean pulmonary arterial pressure of >50 mm Hg and 0.86 for PA enhancement to predict pulmonary vascular resistance of >1000 dyne·s/cm. CONCLUSIONS: Lung PBV and PA enhancement could be indicators of hemodynamics.

Long-term treatment of pulmonary arterial hypertension with macitentan in Japanese patients.

Objective: Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients of macitentan are currently unavailable. This study sought to assess the long-term efficacy and safety of macitentan in Japanese patients with PAH.Methods: In this multicenter, open-label, clinical extension study (JapicCTI-121986), efficacy was evaluated based on the change from baseline at 24, 48, 72, 96 and 120-week in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. In addition, the time to a hospitalization related to PAH and a morbidity/mortality event was determined. As for safety, the incidence of adverse events and changes in laboratory data and vital signs were assessed.Results: Macitentan was administered at a once-daily dose of 10 mg in 30 PAH patients with a median treatment period of 2.4 years (range, 229-1037 days). The improvements in 6MWD, WHO functional class and NT-pro-BNP at week 24 were maintained throughout the long-term follow-up. Hospitalization related to PAH occurred in 2 patients. Levels of liver enzyme and hemoglobin remained unchanged throughout the study period.Conclusions: This study suggests that the long-term use of macitentan is well tolerated and effective in Japanese patients with PAH. We concluded that macitentan can be a possible approach to reduce morbidity/mortality in Japanese PAH patients.

Option of Using Peripherally Inserted Central Catheters in Elderly Patients With Dementia: An Observational Study.

Background: Peripherally inserted central catheters (PICCs) facilitate the treatment of several diseases. Here, we assessed the clinical course of elderly patients with dementia using PICCs. Methods: This retrospective observational study was conducted at a single dementia treatment center. PICCs were used in elderly inpatients with dementia who required (a) intravenous therapy, supplemental parenteral nutrition, and dysphagia rehabilitation during acute illness; (b) end-of-life care; (c) total parenteral nutrition (TPN); or (d) an alternative to peripheral vascular (PV) access. Results: Fifty-nine patients were enrolled (83.5 ± 6.9 years): 61% were in the acute treatment group, and 17% were in the end-of-life care group. The median catheter lifespan was 42 (23-87.5) days. The incidence of catheter-related bloodstream infection was 0.22 per 1,000 PICC-days, and that of deep venous thrombosis was 0.66 per 1,000 PICC-days. Among the patients in acute treatment group, 19% resumed sufficient oral intake after the treatment using PICC, and 36% resumed oral intake of gelatin-like food. Among the patients in the end-of-life care group, 91% received intravenous fluids continuously until death by initially inserted PICC. Conclusion: In elderly patients with dementia, PICCs might be one of the options during the treatment of acute illness as well as for prolonged support during end-of-life care.

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.

Automatic Remasking of Digital Subtraction Angiography Images in Pulmonary Angiography.

In pulmonary angiography, the heartbeat creates artifacts that hinder extraction of blood vessel images in digital subtraction angiography. Remasking according to the cardiac phase of the angiogram may be effective but has yet to be automated. Here, automatic remasking was developed and assessed according to the cardiac phase from electrocardiographic information collected simultaneously with imaging. Manual remasking, fixed remasking, and our proposed automatic remasking were applied to 14 pulmonary angiography series from five participants with either chronic thromboembolic pulmonary hypertension or pulmonary arteriovenous malformation. The processing time and extent of artifacts from the heartbeat were compared. In addition, the peak signal-to-noise ratio (PSNR) was measured from differential images between mask image groups before the injection of the contrast medium to investigate optimal mask images. The mean time required for automatic remasking was 4.7 s/series, a significant reduction in processing time compared with the mean of 266 s/series for conventional manual processing. A visual comparison of the different approaches showed virtually no misregistration artifacts from the heartbeat in manual or automatic remasking according to cardiac phase. The results from measuring the PSNR for differential images between mask image groups also showed that smaller cardiac phase difference and time difference between two images ensure higher PSNR (p < 0.01). Automatic remasking according to the cardiac phase was fast and easy to implement and reduced misregistration artifacts from heartbeat.

Effects of Tobacco Smoking on Cardiovascular Disease.

Tobacco smoking continues to be a major risk factor for cardiovascular disease (CVD) and the leading avoidable cause of death worldwide. Tobacco smoking has declined in high-income countries, but the average smoking rate in Japan remains high: 29.4% for men and 7.2% for women in 2017. Of note, the average smoking rate among middle-aged men remains approximately 40%, indicating that a high incidence of smoking-related CVD will continue for a couple of decades in Japan. The adverse effects of tobacco smoking on CVD are more extensive than previously thought. Physicians should be particularly alert to the development and progression of heart failure, atrial fibrillation, and venous thromboembolism, as well as ischemic CVD among tobacco smokers. Increasing use of heat-not-burn tobacco as cigarette alternatives is an emerging issue. Harmful effects do not disappear just by changing the delivery system of tobacco.

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.

＜Editors' Choice＞ Pulmonary Hypertension: Diagnosis, Management, and Treatment.

Pulmonary hypertension (PH) is a hemodynamic state that is characterized by a resting mean pulmonary artery pressure ≧ 25 mmHg. The common forms of PH are pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), PH caused by left-heart disease, and PH due to lung disease. Previously regarded as untreatable, the treatment of PAH has dramatically advanced since the introduction of the drug epoprostenol in 1999, with three-year survival rates improving from 30%-40% to over 85%. Drugs available for the specific treatment of PAH include endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogs, and prostacyclin-receptor agonists. In the past decade, management and treatment of CTEPH have also improved. While pulmonary endarterectomy used to be the only option for the treatment of CTEPH, newer treatments include a soluble guanylate cyclase stimulator, which has proven to be an efficacious targeted therapy. Other cases benefit from balloon pulmonary angioplasty.