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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

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.

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.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.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.

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/cm5. Conclusions Lung PBV and PA enhancement could be indicators of hemodynamics.

Post-pulmonary embolism (PE) syndrome is an important clinical condition that can affect the long-term prognosis after acute PE.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.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.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 (β = 0.367, P = .003; and β = -0.435, P = .001, respectively).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.

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.

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

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.

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.

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

Background Venous thromboembolism (VTE) is the third frequent acute cardiovascular syndrome in the Europe and Japan. Since direct oral anticoagulants (DOACs) are widely used now, the morbidity and mortality of pulmonary embolism (PE) patients especially associated with cancer needs to be re-evaluated. Purpose We evaluated the clinical course of patients with PE mainly treated with DOACs. Methods This retrospective observational study was conducted in a single center. The data were collected from the medical record of consecutive patients who received inpatient treatment of PE. In this study, we have compared PE patients with cancer (cancer PE) to those without cancer (non-cancer PE) and evaluated the mortality, recurrent of VTE and major bleedings. Results In total, 140 patients were enrolled: 94 patients were cancer-related, and 46 patients were without cancer (Table). The type of the tumor in cancer PE patients were as follows: gastric 8 (9%), esophageal 5 (5%), pancreatic 12 (13%), lung 14 (15%), lymphoma 2 (2%), gynecologic 17 (18%), renal 2 (2%), bile duct 8 (9%), colon 12 (13%), and others 17 (18%). Kaplan-Meier curve showed that the cumulative all-cause mortality was significantly higher in the cancer PE group (35/94 (37%) vs. 2/46 (4%), P Conclusions The risk of recurrent VTE was still higher in cancer PE patients compared to non-cancer PE patients, although DOACs were used. Meanwhile the incidence of major bleeding was comparable in both groups, the risk of bleeding might be acceptable with using DOACs especially in cancer PE patients. Figure 1 Funding Acknowledgement Type of funding source: None

Background Recently, post pulmonary embolism (PE) syndrome or chronic thromboembolic disease after acute PE, has been recognized as important long-term complications. Furthermore, patients may develop with chronic thromboembolic pulmonary hypertension. Purpose We aimed to evaluate the frequency of residual pulmonary thromboemboli after acute PE by using our “higher”-resolution CT scan imaging method to detect residual thromboemboli down to sub-segmental pulmonary arteries. Methods This study was a prospective multi-center observational study. We enrolled consecutive 34 patients with acute symptomatic PE whose informed consent was obtained, and followed up for one year. One year after the onset of acute PE, patients were referred to our hospital and multiple examination including CT scan, 6-minute walk test (6MWT), questionnaire of SF-36, echocardiography and laboratory testing were performed. Additionally, we have modified the CT obstruction index (CTOI) to quantitatively evaluate the thromboemboli down to sub-segmental pulmonary arteries. Results Mean age was 60.5±15.8 years, and 56% were male. No patient was categorized as low recurrent VTE risk which was caused by transient factors, one patient was associated with active cancer, and 12% had known thrombophilia. In 85% of the patients, this onset was the first obvious episode of PE. At diagnosis, elevated B-type natriuretic peptide (BNP) (≥100 pg/ml) or N-terminal (NT)-proBNP (≥500 pg/ml) was observed in 45% of the patients. Median tricuspid regurgitation peak gradient (TRPG) by echocardiography was 30.9 (19.3–50.1) mmHg. Among all, 35% of the patients received single-drug approach with DOACs. At discharge, all of the patients except two were treated with DOACs. One year after the onset, 21% of the patient were in NYHA II and others were in NYHA I. It was notable that pulmonary thromboemboli was detected by our CT scan in 76% of the patients. Modified CTOI was median 11.9 (1.8–24.4) % as shown in the figure. In multiple regression analysis, TRPG at diagnosis and BNP at one month were significantly associated with mCTOI (β=0.536, p=0.002 and β=−0.482, p=0.003, respectively). Additionally, lowest SpO2 during 6MWT after one year from the onset, tended to inversely associate with mCTOI (β=−0.341, p=0.052). Conclusions Using our modified CT scan imaging method and modified CTOI, residual pulmonary thromboemboli was able to be detected more frequently than the previous studies. Residual pulmonary thromboemboli could be one of the cause of the post PE syndrome and lead to exercise-induced desaturation. Figures Funding Acknowledgement Type of funding source: None

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.

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

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...

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.

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) 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.

Visual Abstract, Highlights • As a joint project between industry and academia, we are developing a CLB that enables BP measurement continuously and noninvasively by capturing photoplethysmographical biosignals. • To validate the estimation of BP using a CLB in accordance with the latest wearable device standard issued by the Institute of Electrical and Electronics Engineers (IEEE 1708-2014). • We found that CLB is technically comparable to the ordinary cuff-based BP-measuring device. • CLB will apply for wearable health care monitoring device that may change landscape of BP measurements in terms of continuous and stress-free monitoring., Summary Ordinary cuff-based blood pressure–monitoring devices remain a technical limitation that disturbs activities of daily life. Here we report a novel system for the cuff-less blood pressure estimation (CLB) that requires only 1 sensor for photoplethysmography. The present study is the first report to validate and assess the clinical application of the CLB in accordance with the latest wearable device standard (issued by the Institute of Electrical and Electronics Engineers, standard 1708-2014). Our CLB is expected to offer a flexible and wearable device that permits blood pressure monitoring in more continuous and stress-free settings.

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

Left main coronary artery (LMCA) disease due to external compression by a dilated main pulmonary artery (MPA) is an uncommon clinical entity. Here, we describe a 52-year-old woman with pulmonary arterial hypertension (PAH) and anteroseptal old myocardial infarction (OMI). The cause of the OMI was external compression of the LMCA by the dilated MPA and aneurysm of the left coronary sinus of Valsalva. The patient’s sister (aged 56 years) had also been diagnosed with PAH and both women had a novel heterozygous splicing mutation, IVS2-2A > G (c.374-2A > G in NM_001456), in the filamin A (FLNA) gene. To our knowledge, this is the first report of HPAH which is likely to be due to FLNA mutation and compression of the LMCA between a dilated MPA and aneurysm of the left coronary sinus of Valsalva.

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.

Purpose Myocardial contractile reserve is associated with clinical prognosis in patients with dilated cardiomyopathy (DCM). We assessed myocardial contractile reserve using tissue Doppler strain rate imaging with dobutamine stress echocardiography in DCM patients. Methods Simultaneous echocardiography and left ventricular (LV) catheterization during dobutamine stress were performed in 20 patients with DCM, and echocardiography was performed in 31 control subjects. Dobutamine was infused at a starting dose of 5 μg/kg/min for 5 minutes and then at 10 μg/kg/min. Peak endomyocardial radial strain (ɛ) and systolic strain rate (SRsys) measured with echocardiography and the maximum first derivative of LV pressure (LV dP/dtmax) derived from catheterization were used as indices of contractility. Their percentage change from baseline to the dose of 10 μg/kg/min was calculated. Results The ɛ and SRsys were significantly smaller in DCM patients than in controls. The LV dP/dtmax, ɛ, and SRsys were significantly higher at the dose of 10 μg/kg/min than at baseline. The percentage change in SRsys was significantly correlated with the percentage change in LV dP/dtmax. Conclusions Strain rate imaging during dobutamine stress in DCM might prove noninvasively informative for the evaluation of myocardial contractile reserve and provide insight into LV systolic dysfunction. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:555–560, 2016

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.

Purpose To report a case of secondary pulmonary arterial hypertension (PAH) and the relationship of intraocular pressure (IOP) change with right ventricular diameter (RVD) and brain natriuretic peptide (BNP). Methods Case report. Patient A 22-year-old woman with dilated and congested conjunctival and episcleral veins was diagnosed with high IOP. She was previously diagnosed with Sjogren syndrome and suffered from secondary PAH. Results The RVD and BNP level improved and the IOP decreased with routine treatment for PAH. During self-cessation of treatment for PAH, the RVD, BNP level, and IOP deteriorated. However, they improved after treatment was reinitiated. Conclusion There was a synchronizing change in the parameters representing high pulmonary arterial pressure and IOP during treatment of PAH.

BACKGROUND Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH. METHODS AND RESULTS Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24. Change to week 24 in the other hemodynamic parameters, 6-min walk distance (6MWD), World Health Organization (WHO) functional class, and plasmaN-terminal pro-brain natriuretic peptide (NT-pro-BNP), as well as time to clinical deterioration up to week 52 were also assessed as secondary endpoints. In the 28 patients on per-protocol analysis, PVR decreased from 667±293 to 417±214 dyn·sec·cm(-5)(P

BackgroundThere is a link between sympathetic overactivity and sleep-disordered breathing (SDB), and both of which are important indicators of the development of heart failure. To manage the increasing numbers of heart failure patients, any method used to check for them needs to be as non-invasive, simple, and cost-effective as possible. The purpose of this study is to assess screening of SDB with a non-restrictive monitor and the autonomic nervous system in heart failure patients.MethodsThe subjects were 49 patients (mean age: 67 years; male: 78%) hospitalized for worsening heart failure. After stabilization with appropriate medical therapy, each patient simultaneously underwent sleep apnea syndrome (SAS) screening with the SD-101 (Kenzmedico Co. Ltd., Saitama, Japan), which is a novel, non-restrictive, sheet-like monitor for SAS screening, and assessment of heart rate variability (HRV) with a Holter monitor. In addition, we assessed daytime sleepiness by using the Epworth Sleepiness Scale.ResultsThe mean respiratory disturbance index (RDI) was 21.9events/h. Males had significantly greater RDI values than females (24.5±11.2events/h vs. 13.0±6.2events/h, p

BackgroundRivaroxaban is currently used to prevent stroke in patients with atrial fibrillation. Measuring coagulation function may help clinicians to understand the effects of this drug and the associated risk of bleeding.Methods and resultsRivaroxaban was given to 136 patients with non-valvular atrial fibrillation. Mean age was 74.5±9.0 years (men: 63.2%) and mean CHADS2 score (±SD) was 1.8±1.2. Prothrombin times (PTs) and plasma soluble fibrin (SF) levels were examined in 84 out of 136 patients at baseline and at least 2 weeks thereafter. In 48 patients we were able to collect blood at exact times, namely just before and 3h after rivaroxaban administration, corresponding to the trough and peak concentrations. Mean peak PT in 48 patients was 17.1±3.6s and median peak SF level was 1.46μg/mL. Multiple regression analysis showed that female sex, high brain natriuretic peptide, and high dose were independent factors prolonging the peak PT. Patients with peak PTs ≥20s experienced significantly more bleeding events. Among 29 of 46 patients newly treated with rivaroxaban without any previous anticoagulant, we examined coagulation function at the exact trough and peak times. In 29 patients, peak PT was significantly more prolonged than the baseline or trough PT (p

Statin therapy moderately increases high-density lipoprotein cholesterol (HDL-C) levels. Contrary to this expectation, a paradoxical decrease in HDL-C levels after statin therapy is seen in some patients. We evaluated 724 patients who newly started treatment with statins after acute myocardial infarction (AMI). These patients were divided into 2 groups according to change in HDL-C levels between baseline and 6 to 9 months after initial AMI (ΔHDL). In total, 620 patients had increased HDL-C levels and 104 patients had decreased HDL-C levels. Both groups achieved follow-up low-density lipoprotein cholesterol levels100 mg/dl. Adverse cardiovascular events (a composite of all-cause death, myocardial infarction, and stroke) have more frequently occurred in the decreased HDL group compared with the increased HDL group (15.4% vs 7.1%, p = 0.01). Multivariate analysis showed that decreased HDL, onset to balloon time, and multivessel disease were the independent predictors of adverse cardiovascular events (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.08 to 3.52; HR 1.05, 95% CI 1.01 to 1.09; and HR 2.08, 95% CI 1.22 to 3.56, respectively). In conclusion, a paradoxical decrease in serum HDL-C levels after statin therapy might be an independent predictor of long-term adverse cardiovascular events in patients with AMI.

Aims The 6-min walking distance is often used for assessing the exercise capacity under the treatment with an endothelin receptor antagonist (ERA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The cardiopulmonary exercise testing (CPX) was reported to be more useful for the patients with pulmonary arterial hypertension (PAH), however, few reports exist in patients with inoperable CTEPH. The aim of this study was to investigate the effects of an oral dual ERA, bosentan, on exercise capacity using CPX in patients with PAH and inoperable CTEPH. Main methods This study included all patients diagnosed with 17 PAH and 12 CTEPH in the World Health Organization functional classes II–IV who started treatment with bosentan therapy. They underwent CPX, which was performed before bosentan therapy and at 3 to 6 months of the treatment. Key findings In PAH patients, peak VO 2 significantly increased after the bosentan treatment (p = 0.009). On the other hand, in CTEPH patients, there were no significant differences in the peak VO 2 . However, the peak PETCO 2 was significantly increased from 23.9 ± 5.2 mm Hg at baseline to 29.3 ± 10.7 mm Hg after the bosentan treatment (p = 0.040). In addition, peak heart rate during exercise tended to decrease after the bosentan therapy (p = 0.089). Significance Bosentan therapy improved peak PETCO 2 but not peak VO 2 in patients with inoperable CTEPH. These findings demonstrated that CPX is useful for assessing the exercise capacity of patients with PAH and inoperable CTEPH under the treatment with an ERA.

Recently, we reported that angiotensin II receptor blocker (ARB), valsartan, and calcium channel blocker (CCB), amlodipine, had similar effects on the prevention of cardiovascular disease (CVD) events in diabetic hypertensive patients. We assessed the difference of cardiovascular protective effects between ARB and CCB in patients with and without previous CVD, respectively. A total of 1,150 Japanese diabetic hypertensive patients were randomized to either valsartan or amlodipine treatment arms, which were additionally divided into 2 groups according to the presence of previous CVD at baseline (without CVD, n = 818; with CVD, n = 332). The primary composite outcomes were sudden cardiac death, acute myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure. The incidence of primary end point events in patients with previous CVD was 3.5-times greater than that in patients without previous CVD (64.1 vs 17.9/1,000 person-years). The ARB- and the CCB-based treatment arms showed similar incidence of composite CVD events in both patients without previous CVD (hazard ratio [HR] 1.35, 95% confidence interval [CI] 0.76 to 2.40) and those with previous CVD (HR 0.79, 95% CI 0.48 to 1.31). The ARB-treatment arm showed less incidence of stroke compared with the CCB-based treatment arm in patients with previous CVD (HR 0.24, 95% CI 0.05 to 1.11, p = 0.068), whereas the 2 treatment arms showed similar incidence of stroke in patients without previous CVD (HR 1.52, 95% CI 0.59 to 3.91). In conclusion, the ARB- and the CCB-based treatments exerted similar protective effects of CVD events regardless of the presence of previous CVD. For stroke events, the ARB may have more protective effects than the CCB in diabetic hypertensive patients with previous CVD.

OBJECTIVE: To clarify whether the impact of normal and high-normal BP (BP) per se on cardiovascular disease (CVD) and all-cause death differs depending on smoking status. METHODS AND RESULTS: A prospective observational cohort study (median follow-up period: 7.5 years) was performed among 25,077 healthy nondiabetic Japanese men aged 20-61 years (mean age 37.3 years), whose BP was less than 150/95 mmHg and who were not on medication. Hazard ratios (HRs), adjusted by known risk factors and a change in annual BP during the follow-up, were calculated by the Cox proportional model with less than 119/75 mmHg as a reference. Among smokers, CVD events increased significantly from a SBP of 120 mmHg, with HRs of 2.68 (120-129 mmHg), 4.28 (130-139 mmHg), and 11.7 (140-149 mmHg). The CVD events also increased from a DBP of 75 mmHg (P for trend less than 0.0001), with 75-79 mmHg and 90-94 mmHg considered statistically significant. Among noncurrent smokers, 110-149 mmHg (SBP) and 75-89 mmHg (DBP) were not associated with elevated HRs for CVD. The relation between BP and all-cause mortality was similar among both current and noncurrent smokers: 140-149 mmHg (SBP) and 90-94 mmHg (DBP) were significantly associated with elevated risk, and 130-139 mmHg (SBP) among noncurrent smokers associated with elevated risk. CONCLUSION: Young and middle-aged healthy Japanese individuals with normal and high-normal BP (120-139/75-89 mmHg) were at risk for CVD among smokers, even after adjusting for an annual change in BP.

Background: Low adiponectin levels and high leptin levels are associated with a high incidence of developing cardiovascular disease. However, the relationship between the levels of these adipokines and the development of adverse events after acute myocardial infarction (AMI) remains unclear. Methods and Results: This study enrolled 724 Japanese subjects with AMI who underwent successful emergency percutaneous coronary intervention (PCI). Their serum adiponectin and leptin levels were measured 7 days after AMI onset. There were 63 adverse events during the 3-year follow-up. The levels of adiponectin and leptin and the leptin to adiponectin ratio, were significantly associated with adverse events [hazard ratio 2.08 (95% confidence interval (CI) 1.33–3.24), P=0.001; hazard ratio 0.62 (95% CI 0.43–0.90), P=0.012; hazard ratio 0.59 (95% CI 0.45–0.76), P

Background Serum uric acid level is a predictor of future hypertension. However, its dependence on body mass index or age is unclear. Methods We examined 26,442 Japanese males aged 18–60 years free from hypertension or diagnosed cardiovascular disease at baseline followed up between 2000 and 2010. Participants were categorized into three groups according to the tertile of serum uric acid levels [mg/dL; 1st (reference): 0.1–5.3; 2nd: 5.4–6.2; 3rd: 6.3–11.6]. Incident hypertension was defined as newly detected blood pressure ≥ 140/90 mm Hg and/or antihypertensive drugs initiation. Body mass index (

It has not been fully examined whether angiotensin II receptor blocker is superior to calcium channel blocker to reduce cardiovascular events in hypertensive patients with glucose intolerance. A prospective, open-labeled, randomized, controlled trial was conducted for Japanese hypertensive patients with type 2 diabetes mellitus or impaired glucose tolerance. A total of 1150 patients (women: 34%; mean age: 63 years; diabetes mellitus: 82%) were randomly assigned to receive either valsartan- or amlodipine-based antihypertensive treatment. Primary outcome was a composite of acute myocardial infarction, stroke, coronary revascularization, admission attributed to heart failure, or sudden cardiac death. Blood pressure was 145/82 and 144/81 mm Hg, and glycosylated hemoglobin was 7.0% and 6.9% at baseline in the valsartan group and the amlodipine group, respectively. Both of them were equally controlled between the 2 groups during the study. The median follow-up period was 3.2 years, and primary outcome had occurred in 54 patients in the valsartan group and 56 in the amlodipine group (hazard ratio: 0.97 [95% CI: 0.66–1.40]; P =0.85). Patients in the valsartan group had a significantly lower incidence of heart failure than in the amlodipine group (hazard ratio: 0.20 [95% CI: 0.06–0.69]; P =0.01). Other components and all-cause mortality were not significantly different between the 2 groups. Composite cardiovascular outcomes were comparable between the valsartan- and amlodipine-based treatments in Japanese hypertensive patients with glucose intolerance. Admission because of heart failure was significantly less in the valsartan group.

Methods and Results: We evaluated 879 AMI patients undergoing successful primary revascularization within 24 h of symptom onset. The patients were classified into 3 groups according to tertiles of plasma VEGF levels at 7 days after the onset of AMI. Major adverse cardiovascular and cerebrovascular events (MACCE), defined as cardiac death, recurrent acute coronary syndrome, hospital readmission for heart failure, or stroke, were assessed during the 6-month follow-up period. The incidence of MACCE was the least frequent in the middle tertile. Compared to the middle tertile, patients in the low tertile were at a significantly higher risk for MACCE even after adjusting for baseline characteristics (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.18–6.06, P=0.019). An absence of statin treatment before onset and a younger age (HR 0.54, 0.87; 95%CI 0.33–0.90, 0.76–0.99; P=0.017, 0.037; respectively) were significantly associated with low VEGF. Conclusions: Low plasma VEGF levels at 7 days after the onset of AMI were associated with a significantly increased risk for MACCE during 6 months of follow-up.