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.

Association between milk consumption in middle age and frailty in later life: The Aichi Workers' cohort study.

AIM: Several studies have shown that dairy consumption in old age is effective in preventing frailty. However, there is a lack of evidence regarding the association between milk consumption during middle age and the development of frailty in old age. Therefore, we carried out an investigation to explore the association between milk consumption during middle age and development of frailty examined after over 15 years of follow up in a long-term cohort study in Japan. METHODS: We studied 265 participants aged 60-79 years (212 men and 53 women) in 2018, who participated in both the baseline survey in 2002 and the frailty assessment in 2018. The amount of milk consumption (g/day) at baseline was age- and energy-adjusted, and classified into three categories (no, low and high consumption: 0 g/day, ≤135.86 g/day, >135.86 g/day in men and 0 g/day, ≤126.44 g/day, >126.44 g/day in women). Odds ratios (OR) and 95% confidence intervals (CI) for prefrailty/frailty after adjusting for lifestyles at baseline, stratified by sex, were estimated using logistic regression analysis. RESULTS: The prevalence of prefrailty/frailty in 2018 was 37.7% and 28.3% in men and women, respectively. Milk consumption categories were inversely associated with the prevalence of prefrailty/frailty in men (OR 0.34, 95% CI 0.14-0.84 in low consumption; OR 0.31, 95% CI 0.10-0.95 in high consumption; P < 0.05), but not in women (OR 0.53, 95% CI 0.11-2.65; P = 0.44). CONCLUSIONS: In this study, milk intake in middle-aged men was inversely associated with the prevalence of prefrailty/frailty later in life. Geriatr Gerontol Int 2024; 24: 700-705.

Factors influencing interprofessional collaboration in long-term care from a multidisciplinary perspective: a case study approach.

Systematic assessments of interprofessional collaboration barriers and enablers in long-term care settings are critical for delivering person-centered healthcare. However, research on factors influencing interprofessional collaboration in long-term care settings is limited. For this study, 65 healthcare professionals across multiple facilities experienced in long-term care in Japan participated in online focus group discussions and individual interviews to discuss cases. The qualitative data were analyzed using qualitative content analysis. Seven themes emerged: coordination, the need for care manager training, hierarchy among healthcare professionals, specialization but not the mind-set of overspecialization, casual conversations, electronic group communication tools, and excessive fear of personal information protection. These findings highlight the need to develop coordinator roles and for interprofessional education on the proper approach to personal information protection laws. Furthermore, daily casual conversations, the use of online platforms, and the prevention of patients being left behind due to overspecialization are required.

Associations of overweight and obesity with the risk of cardiovascular disease according to metabolic risk factors among middle-aged Japanese workers: The Aichi Workers' cohort study.

BACKGROUND: The association between obesity and cardiovascular disease (CVD) remains unclear, particularly for those with established CVD risk factors. We analyzed follow-up data from the Aichi Workers' Cohort Study. We studied the association between the degree of obesity and risk of CVD and its subtypes specifically among individuals with hypertension, hyper-low-density lipoprotein (LDL)-cholesterolemia, or diabetes. METHODS: Pooled data of 8972 adults (7076 men and 1896 women) who were recruited between 2002 and 2008 were used in the current analysis. We used multivariable Cox proportional hazard model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between the degree of obesity assessed with body mass index (BMI) and the risk of CVD and its subtypes, i.e., coronary heart disease (CHD) and stroke. RESULTS: During a median of 12 years, there were 197 CVDs (80 CHDs and 117 strokes). BMI ≥ 27.5 compared to 21.0-22.9 kg/m2 was positively and significantly associated with the risks of CVD, CHD, and total stroke. Hypertension, hyper-LDL-cholesterolemia, and diabetes mediated 15.9%, 5.8%, and 8.7% of obesity-CVD associations, respectively, and 28.3% by their combination. In the stratified analyses by the presence of risk factors, BMI ≥ 25.0 (overweight/obesity) compared to BMI < 25 kg/m2 was associated with a higher risk of CVD in those with and without hypertension, but only with hyper-LDL-cholesterolemia, and without diabetes. CONCLUSIONS: Overweight/obesity was associated with the risk of CVD and its subtypes. About 30% of the risk was explained by hypertension, hyper-LDL-cholesterolemia, and diabetes, of which hypertension accounted for approximately the half of the explained risk. However, overweight/obesity increased the risk of CVD even in those without hypertension. These findings highlight the importance of controlling and preventing overweight/obesity regardless of chronic disease status.

Detrimental Impact of Comorbid Mental Disorders in Chronic Thromboembolic Pulmonary Hypertension　- A Retrospective Observational Study.

Background: The relationship between the prognosis of patients with both chronic thromboembolic pulmonary hypertension (CTEPH) and a mental disorder (MD) remains unclear. Methods and Results: The study group comprised 157 patients with CTEPH who underwent right heart catheterization and were subdivided into 2 groups according to the presence of MDs: MD and non-MD. The patients with MDs were defined as those who had visited a psychiatrist and were under psychotropic drug treatment. The primary outcome was a composite of all-cause death and worsening of PH. The median follow-up period was 1,164 days. The incidence of the primary composite outcome was higher in the MD group than in the non-MD group (24.0% vs. 6.8%), whereas the all-cause mortality rate was comparable between groups (12.0% vs. 6.1%). The mean pulmonary arterial pressure, cardiac index, and pulmonary vascular resistance at baseline were all similar between groups. The Cox proportional hazards model indicated that MD was an independent risk factor for the primary composite outcome (hazard ratio, 2.990; 95% confidence interval, 1.034-8.642). Conclusions: In the present study, concomitant CTEPH and MD was significantly associated with a poor prognosis and such patients should be carefully followed.

Nonrestorative Sleep and Type 2 Diabetes Incidence: the Aichi Workers' Cohort Study.

BACKGROUND: The term "nonrestorative sleep (NRS)" refers to unrefreshed feeling at wake-up and is a domain of poor sleep quality. Previous researches have demonstrated that NRS is linked to a number of diseases and adverse health outcomes, but less is known regarding the link between NRS and diabetes, particularly in Japanese. METHODS: We studied 3665 middle-aged male participants of the Aichi Workers' Cohort Study who were followed-up from 2002 to 2019. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of incident type 2 diabetes mellitus (T2DM) in relation to NRS adjusted for potential confounding variables. RESULTS: During a median follow-up of 14.6 years, 421 type 2 diabetes cases were identified. Participants with NRS had a higher crude incidence rate of T2DM (11.2/1,000 person-years), compared to participants without NRS (9.3/1,000 person-years). In the fully adjusted model, individuals who reported having NRS had a significantly higher risk of developing T2DM (HR: 1.36, 95% CI: 1.10-1.67). The association was observed only in participants under 50 years old (HR: 1.82, 95% CI: 1.36-2.43), not in the older (50 years or older) participants (P for interaction =0.025). In contrast, stratified analyses by the presence of shift work, obesity or sleep duration showed similar associations in all the strata. CONCLUSIONS: NRS was associated with higher risk of T2DM in middle-aged Japanese male workers independent of a variety of lifestyle factors and other sleep problems.

Association of Low-Density Lipoprotein Cholesterol with Risk of Coronary Heart Disease and Stroke among Middle-Aged Japanese Workers: An Analysis using Inverse Probability Weighting.

AIMS: The associations between low-density lipoprotein cholesterol (LDL-C) and the risk of cardiovascular disease (CVD) subtypes are not well established among the Japanese population. This study used longitudinal data from the Aichi Workers' Cohort Study to explore the association between LDL-C levels and the risk of coronary heart disease (CHD) and stroke subtypes. METHODS: Pooled data of 8966 adults (7093men and 1903 women) who were recruited between (2002) and (2008) were used for the current analysis. Propensity scores for the LDL-C categories were generated using multinomial logistic regression. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from the inverse probability weighted Cox proportional hazards model for LDL-C category associations with risks of CHD, stroke subtypes, and CVD. RESULTS: During a median follow-up of 12 years, 122 strokes (57 ischemic strokes, 25 intracerebral hemorrhage, and 40 unknown subtypes) and 82 cases of CHD were observed. LDL-C 160- mg/dL compared to LDL-C 100-119 mg/dL was positively and significantly associated with the risk of CHD (HR: 4.56; 95% CI: 1.91-10.9) but not with ischemic stroke (HR: 0.99; 95% CI: 0.44-2.22). LDL-C was inversely associated with the risk of intracerebral hemorrhage (P for trend=0.009). CONCLUSION: In middle-aged Japanese workers, LDL-C was significantly and positively associated with CHD, but not with ischemic stroke. LDL-C was inversely significantly associated with intracerebral hemorrhage.

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.

Inhaled iloprost induces long-term beneficial hemodynamic changes in patients with pulmonary arterial hypertension receiving combination therapy.

Inhaled iloprost is an established treatment for pulmonary arterial hypertension (PAH). However, the long-term hemodynamic changes that inhaled iloprost induces are unclear. Here, we retrospectively enrolled 18 patients with PAH who received inhaled iloprost as add-on to oral combination therapy from December 2016 to January 2021 at our institute in Japan. We then examined the changes in hemodynamic parameters induced by iloprost in these patients during right heart catheterization (RHC). To examine the long-term effects of iloprost, we repeated the RHC examination at follow-up (median time to follow-up, 8.5 months). During both catheterization procedures, iloprost was administered by using an I-neb AAD system (Philips NV). In a comparison of pre-inhalation values at the first and follow-up RHCs, inhaled iloprost significantly improved mean pulmonary artery pressure (mPAP; 39.9 ± 7.8 to 32.5 ± 7.2 mmHg, p = 0.016) and pulmonary vascular resistance (PVR; 588.5 ± 191.7 to 464.4 ± 188.5 dyn s cm-5, p = 0.047). During the follow-up RHC, in a comparison of the pre-inhalation and best recorded values out to 30 min after the end of iloprost inhalation, iloprost significantly decreased mPAP (32.5 ± 7.2 to 30.0 ± 6.6 mmHg, p = 0.007) and PVR (457.8 ± 181.4 to 386.2 ± 142.8 dyn s cm-5, p = 0.025) and significantly increased cardiac output (4.19 ± 0.91 to 4.64 ± 1.01 L/min, p = 0.035). Iloprost may have not only acute vasodilation effects but also long-term hemodynamic benefits in PAH patients receiving combination therapy.

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.

End-Systolic Eccentricity Index Obtained by Enhanced Computed Tomography Is a Predictor of Pulmonary Vascular Resistance in Patients with Chronic Thromboembolic Pulmonary Hypertension.

The usefulness of the parameters of biventricular function simultaneously measured using enhanced multi-detector computed tomography (MDCT) pulmonary angiography in patients with chronic thromboembolic pulmonary hypertension (CTEPH) has not been clarified. This study aimed to verify the correlation between left and right ventricular (RV) parameters and pulmonary vascular resistance (PVR). Patients who underwent enhanced MDCT before diagnostic right heart catheterization at Nagoya University Hospital between October 2014 and April 2021 were enrolled. The correlation of biventricular function and volume parameters with PVR was assessed. Eighty patients were retrospectively analyzed. Patients' mean age was 65 ± 13 years, mean PVR was 9.1 (range, 6.1−11.3) Wood units, and mean end-systolic eccentricity index (esEI) was 1.76 ± 0.50. RV end-systolic volume (ESV) (p = 0.007), RV cardiac output (CO) (p < 0.001), RV ejection fraction (p < 0.001), LV end-diastolic volume (EDV) (p < 0.001), left ventricular (LV) ESV (p = 0.006), LVCO (p < 0.001), end-diastolic EI (p < 0.001), and esEI (p < 0.001) were significantly correlated with PVR. The LVEDV (p = 0.001) and esEI (p < 0.009) were independent predictors of PVR. Systolic pulmonary arterial pressure (PAP) (p < 0.001), diastolic PAP (p < 0.001), mean PAP (p < 0.001), right atrial pressure (p < 0.023), and PVR (p < 0.001) were significantly higher in the high esEI group than in the low esEI group. The esEI was a simple predictor of CTEPH severity.

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.

Effects of an environmental endocrine disruptor, para-nonylphenol on the cell growth of Euglena gracilis: association with the cellular oxidative stress.

Effects of an environmental endocrine disruptor, para-nonylphenol (NP) on the cell growth of a photosynthetic eukaryotic microorganism, Euglena gracilis were analysed under different cell culture conditions. Although NP did not show significant inhibitory effects on the cell growth of E. gracilis (Z and SM strains) under light culture condition, NP exhibited significant suppressive effects under dark culture condition. Exogenous supplementation with lipophilic antioxidants (α-tocopherol, ß-carotene or 6-O-palmitoyl-ascorbic acid) to E. gracilis caused strong preventive effects against NP-induced cell growth inhibition under dark culture condition, but hydrophilic antioxidants [ascorbic acid, glutathione and epigallocatechin gallate (EGCG)] did not show significant preventive effects. NP caused significant generation of reactive oxygen species (ROS) in E. gracilis under dark culture condition, but E. gracilis under light culture condition did not show significant increase in ROS generation. Supplementation with lipophilic antioxidants to E. gracilis caused significant suppressive effects against NP-induced cellular ROS generation under dark culture condition, but hydrophilic antioxidants did not show significant suppressive effects. Furthermore, the productivities of typical cellular antioxidants (α-tocopherol, ß-carotene and ascorbic acid) in E. gracilis under light culture conditions were much higher than those under dark culture conditions.

＜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.