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JAK2V617F is the most frequent driver mutation in myeloproliferative neoplasms (MPNs) and is associated with vascular complications. However, the impact of hematopoietic JAK2V617F on the aortic aneurysms (AAs) remains unknown. Our cross-sectional study indicated that 9 (23%) out of 39 MPN patients with JAK2V617F exhibited the presence of AAs. Next, to clarify whether the hematopoietic JAK2V617F contributes to the AAs, we applied a bone marrow transplantation (BMT) with the donor cells from Jak2V617F transgenic (JAK2V617F) mice or control wild-type (WT) mice into lethally irradiated apolipoprotein E-deficient mice. Five weeks after BMT, the JAK2V617F-BMT mice and WT-BMT mice were subjected to continuous angiotensin II infusion to induce AA formation. Four weeks after angiotensin II infusion, the abdominal aorta diameter in JAK2V617F-BMT mice was significantly enlarged compared to that in the WT-BMT mice. Additionally, the abdominal AA-free survival rate was significantly lower in the JAK2V617F-BMT mice. Hematopoietic JAK2V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of infiltrated macrophages were significantly upregulated in the abdominal aorta of the JAK2V617F-BMT mice accompanied by STAT3 phosphorylation. The accumulation of BM-derived hematopoietic cells carrying JAK2V617F in the abdominal aorta was confirmed by use of reporter GFP-transgene. BM-derived macrophages carrying JAK2V617F showed increases in mRNA expression levels of Mmp2, Mmp9, and Mmp13. Ruxolitinib decreased the abdominal aorta diameter and the incidence of abdominal AA in the JAK2V617F-BMT mice. Our findings provide a novel feature of vascular complications of AAs in MPNs with JAK2V617F.

Background To investigate the clinical implication of the temporal difference in atrial fibrillation (AF)‐onset in acute decompensated heart failure (ADHF) and its impact on post‐discharge prognosis. Methods 336 new‐onset ADHF patients without any history of AF before admission were enrolled (201 males, 63 ± 16 year‐old) and classified into two groups based on their history of AF: the Control group (No AF was detected during hospitalization, n = 278), and the In‐hos‐AF group (AF occurred during hospitalization, n = 58). Post discharge prognosis including rehospitalization due to worsening HF, cardiac death, all‐cause death and cerebrovascular event were compared. Results Kaplan‐Meier analysis demonstrated that the incidence of rehospitalization due to HF, cardiac death, all‐cause death and cerebrovascular event in the In‐hos‐AF group was not significantly different from that in the Control group (P > 0.05 respectively). However, when AF recurred in the In‐hos‐AF group patients (n = 24, 41%) after discharge, the incidence of rehospitalization due to HF and cardiac deaths were higher than those without AF recurrence (P = 0.018 and P = 0.027 respectively). Cox proportional analysis revealed that AF developing after discharge was proven to be an independent risk factor for rehospitalization due to HF (HR 1.845, P = 0.043), cardiac death (HR 3.562, P = 0.013) and all‐cause deaths (HR 2.138, P = 0.020). Conclusion Clinical outcomes of new‐onset in‐hospital AF patients were as good as those without AF history until AF recurrence. However, AF recurrence led to worse prognosis. Therefore, treatment for new‐onset in‐hospital AF in ADHF patients might be postponed until AF recurrence., Clinical outcome in the new‐onset in‐hospital AF in patients with ADHFD, compared with those who had no history of AF.

Background: Exposure to certain carcinogens together with host genetic predisposition likely has an influence on cervical carcinogenesis. Objective: Our aim was to evaluate synergistic effects of glutathione S-transferase (GST) polymorphisms and risk behaviors (i.e., smoking and contraceptive use) on squamous cell cervical cancer (SCCA) development in northeastern Thailand. Methods: Subjects were 198 (SCCA) patients and 198 age-matched healthy controls. Multiplex PCR and PCR-RFLP were used to determine GSTT1 and GSTA1 gene polymorphism, respectively. Results: Interaction between the four polymorphic loci of GSTs (GSTM1, GSTT1, GSTP1 and GSTA1) and increased risk for cervical cancer was not observed. The three genotypes of GSTM1 consistently showed significant risks of smoking with a lower OR for the Null individuals (1.741) at around one -fourth of wild type homozygous individuals (8.000). The effects of GST polymorphisms on cervical cancer risk under the use of hormonal contraceptives apparently did not occur. Conclusions: The predisposition of smoking risk is related to the GST genotype. It is suggested that knowing one’s own genotype data will contribute to the prevention of SCCA by controlling risk habits.

Background Although the National Lung Screening Trial reported a significant reduction in lung cancer mortality when low-dose (LD) CT chest examinations are used for a diagnosis, their biologic effects from radiation exposure remain unclear. Purpose To compare LD CT and standard-dose (SD) CT for DNA double-strand breaks and chromosome aberrations (CAs) in peripheral blood lymphocytes. Materials and Methods Between March 2016 and June 2018, 209 participants who were referred to a respiratory surgery department for chest CT studies were prospectively enrolled in this study. Individuals were excluded if they had undergone radiography examinations within the last 3 days or had undergone chemotherapy or radiation therapy. Peripheral blood samples were obtained before and 15 minutes after CT. The number of γ-H2AX foci and unstable CAs in lymphocytes was quantified by immunofluorescent staining of γ-H2AX and by fluorescence in situ hybridization by using peptide nucleic acid probes for centromeres and telomeres, respectively. The Wilcoxon signed rank test was used for statistical analysis. Bonferroni correction was applied for multiple comparisons. Results Of the 209 participants (105 women, 104 men; mean age, 67.0 years ± 11.3 [standard deviation]), 107 underwent chest LD CT and 102 underwent chest SD CT. Sex distribution, age, and body size metrics were similar between the two groups. The median effective dose of LD CT and SD CT was 1.5 and 5.0 mSv, respectively. The number of double-strand breaks and CAs increased after a SD CT examination (γ-H2AX, P < .001; CAs, P = .003); the number of double-strand breaks and CAs before and after LD CT was not different (γ-H2AX, P = .45; CAs, P = .69). Conclusion No effect of low-dose CT on human DNA was detected. In the same setting, DNA double-strand breaks and chromosome aberrations increased after standard-dose CT. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Brenner in this issue.

Pulmonary hypertension (PH) caused by left-sided heart disease (LHD-PH) is classified into 2 types: isolated post-capillary PH (Ipc-PH) and combined pre- and post-capillary PH (Cpc-PH). However, the impact of pulmonary vascular resistance (PVR) or diastolic pressure gradient (DPG) on the prognosis of LHD-PH has varied among previous studies. Thus, we verified the significance of PVR or DPG on the prognosis of LHD-PH in our series.We analyzed 243 consecutive LHD-PH patients. The patients were divided into 3 groups: Group A, patients with PVR ≤ 3 Wood unit (WU) and DPG7 mmHg; Group B, patients with either PVR3 WU or DPG ≥ 7 mmHg; and Group C, patients with PVR3 WU and DPG ≥ 7 mmHg.The Kaplan-Meier curve demonstrated that Group B had lower cardiac death-free survival compared with Group A, whereas no significant differences were observed when compared with Group C. In the Cox hazard model, DPG was not associated with cardiac death in the LHD-PH patients. However, only in the ischemic heart disease group, patients with DPG ≥ 7 mmHg had worse prognosis compared with those with normal DPG.The cardiac death-free rate of patients with either increased PVR or DPG was close to that of patients with both increased PVR and DPG. It seems reasonable to define Cpc-PH only by PVR in the new criteria. However, the significance of DPG in LHD-PH might be dependent on the underlying cause of LHD-PH.

Background: Coronary revascularization is important in heart failure (HF) with ischemic etiology. Coronary scoring systems are useful to evaluate coronary artery disease, but said systems for residual stenosis after revascularization are still poorly understood. Therefore, the aim of the current study was to clarify the prognostic impact of residual stenosis using a coronary scoring system, Gensini score, in HF patients after percutaneous coronary intervention (PCI). Methods and Results: We analyzed consecutive hospitalized ischemic HF patients (n=199) who underwent PCI. We calculated residual Gensini score after PCI, and divided the patients into 2 groups based on median residual Gensini score. The patients with high scores (≥10, n=101) had a higher prevalence of anemia, lower prevalence of dyslipidemia, and lower left ventricular ejection fraction, compared with those with low scores (

Background The clinical significance of premature ventricular complexes (PVCs) in heart failure (HF) remains unclear. We aimed to clarify the associations of PVC burden with re‐hospitalization and cardiac death in HF patients. Methods We studied 435 HF patients (271 men, mean age 65 years). All patients were hospitalized for worsening HF. After optimal medications, echocardiography, 24 hours Holter monitoring and cardiopulmonary exercise testing were performed before discharge. The clinical characteristics and outcomes of the HF patients were investigated. Results During a median follow‐up period of 2.3 years, there were 125 (28.7%) cardiac events (re‐hospitalization due to worsening HF, fatal arrhythmias, or cardiac death). The patients with cardiac events had higher PVC burden compared to those without (median 0.374%/d [interquartile range 0.013‐1.510] vs median 0.026%/d [interquartile range 0.000‐0.534], P 0.145%/d) to be a predictive factor of cardiac events (area under the curve: 0.64). Kaplan‐Meier analysis demonstrated that cardiac events were more frequent in patients with high‐PVC burden (>0.145%/d, n = 194) compared to those with low‐PVC burden (≤0.145%/d, n = 241). Furthermore, the high‐PVC burden patients had left ventricular (LV) and atrial dilatation, reduced LV ejection fraction, and impaired exercise capacity, compared to the low‐PVC burden patients. In Cox proportional hazards analysis, high‐PVC burden was significantly associated with cardiac events with a hazard ratio of 2.028 (95% confidence interval: 1.418‐2.901, P, The frequency of premature ventricular complex after optimal medication was significantly associated appropriate implantable cardioverter defibrillator therapy, readmission due to worsening heart failure or cardiac death in hospitalized patients with heart failure, even if the frequency was low (>0.145%/d).

Pulmonary hypertension and hereditary hemorrhagic telangiectasia (HHT) have an association mediated by activin A receptor type II-like 1 (ACVRL1) gene pathogenic variants. A 30-year-old woman was previously admitted to a hospital due to lung hemorrhage, and was diagnosed with pulmonary hypertension, but stopped follow-up visits. At 48 years of age, she was admitted to our hospital and was diagnosed with HHT. Genetic testing revealed an ACVRL1 pathogenic variant. After the initiation of pulmonary vasodilator treatment, the patient's mean pulmonary artery pressure started to decrease from 43 mmHg, declining to 37 mmHg when she was 58 years of age. This is the first report describing the 28-year follow-up of an HHT and pulmonary hypertension patient with an ACVRL1 mutation.

Objective This study aimed to explore whether VDR polymorphisms (Fok1, Apa1 and Taq1) are associated to the cervical cancer in Thai population. Materials and methods Subjects of 204 cervical cancer patient and 204 age-matched healthy control were enrolled in the case-control study. VDR polymorphisms were detected by using real-time PCR. Haplotype analysis of three loci was applied to the obtained genotypes. Results Significantly increased risk for cervical cancer was observed in carriers of TT genotype (p = 0.0388) and T allele (p = 0.0357) of Fok1 and TC genotype (p = 0.0001), CC genotype (p = 0.0160) and the C allele of Taq1 (p = 0.0001). Haplotype analyses revealed a significant correlation between C-T-C, T-G-C and T-T-C haplotypes and elevated risk for cervical cancer (OR = 2.06; 95%CI = 1.06-4.00; p = 0.0313, OR = 2.15; 95%CI = 1.22-3.80; p = 0.0078 and OR = 2.81; 95%CI = 1.53-5.16; p = 0.0006, respectively). Furthermore, haplotype carrying C allele of Taq1 (C-G-C + C-T-C + T-G-C + T-T-C) significantly increased cervical cancer risk with OR of 1.92 (95%CI = 1.32-2.79, p = 0.0006). Conclusion Our finding revealed an association between VDR polymorphisms and cervical cancer risk. Taq1 C allele might be a molecular marker for cervical cancer development. .

Background: Anthracycline is used to treat various types of cancer; however, cardiotoxicity negatively affects patient prognosis. Objectives: The aim of the present study was to investigate serial changes in levels of cardiac troponin I (TnI) and B-type natriuretic peptide (BNP) in patients treated with anthracycline-containing therapy. Methods: 91 consecutive cancer patients planned for anthracycline treatment were enrolled and followed up for 12 months. All patients underwent echocardiography and blood sampling at baseline, 3, 6, and 12 months. Results: The patients were divided into two groups based on their TnI level during the follow-up period: the elevated TnI group (TnI ≥0.03 ng/mL; n = 37) and the normal TnI group (n = 54). In the elevated TnI group, the TnI levels increased at 3 and 6 months, but they returned to within normal range at 12 months after anthracycline administration. Unlike TnI, the BNP levels began to increase after 6 months, and remained increased at 12 months. The occurrence of cancer therapeutics-related cardiac dysfunction was higher in the elevated TnI group than in the normal TnI group. When we set the cut-off value of TnI at 0.029 ng/mL, sensitivity and specificity to predict an elevated BNP level of more than 100 pg/mL were 90 and 63%, respectively. Multivariate logistic regression analysis revealed that elevated TnI was an independent predictor of elevated BNP levels. Conclusion: Elevated TnI was an independent predictor for the development of BNP increase. The different characteristics of TnI and BNP should be considered when managing patients treated with anthracycline-containing therapy.

Background: CYP1A1 is an enzyme in phase I of the cytochrome P450 (CYP) superfamily, and plays a key role in detoxification of carcinogens. Host genetic predisposition in the CYP1A1 may be associated with an increased susceptibility to cervical cancer.The study aimed to evaluate four common polymorphisms of the CYP1A1 and cervical cancer susceptibility among Northeast Thai women. Methods: A case-control study was conducted involving 204 patients with squamous cell cervical cancer (SCCA) and 204 age-matched healthy controls. DNA was extracted from peripheral blood leucocytes. CYP1A1 m1, m3, and m4 genotypes were detected using PCR-RFLP, whereas the CYP1A1 m2 genotype was investigated using real-time PCR. Haplotype analysis was performed using PHASE algorithm version 2.1.1. Results: CYP1A1 m3 was monomorphic. Association between the common CYP1A1 polymorphisms, m1 and m2, and cervical cancer risk was not observed (p>0.05), nor was any association found between the m1–m2–m4 haplotype and cervical cancer risk (p>0.05). Interestingly, the CA genotype of CYP1A1 m4 was observed in 30.88% of the cervical cancer patients but was absent in healthy controls. Conclusion: Our results demonstrated a possible involvement of the CYP1A1 m4 polymorphism but no other common polymorphisms (viz., m1, m2, and m3) in the risk for cervical cancer.This finding may be useful when screening for risk of cervical cancer among Northeast Thai women.

BackgroundD-dimer is a sensitive biomarker for cancer-associated thrombosis, but little is known about its significance on cancer therapeutics-related cardiac dysfunction (CTRCD).MethodsConsecutive 169 patients planned for cardiotoxic chemotherapy were enrolled and followed up for 12 months. All patients underwent echocardiography and blood test at baseline and at 3-, 6-, and 12 months.ResultsThe patients were divided into two groups based on the level of D-dimer (>1.65 μg/ml or ≦ 1.65 μg/ml) at baseline before chemotherapy: high D-dimer group (n = 37) and low D-dimer group (n = 132). Left ventricular ejection fraction (LVEF) decreased at 3- and 6 months after chemotherapy in high D-dimer group [baseline, 65.2% (62.8–71.4%); 3 months, 62.9% (59.0–67.7%); 6 months, 63.1% (60.0–67.1%); 12 months, 63.3% (58.8–66.0%), p = 0.03], but no change was observed in low D-dimer group. The occurrence of CTRCD within the 12-month follow-up period was higher in the high D-dimer group than in the low D-dimer group (16.2 vs. 4.5%, p = 0.0146). Multivariable logistic regression analysis revealed that high D-dimer level at baseline was an independent predictor of the development of CTRCD [odds ratio 3.93, 95% CI (1.00–15.82), p = 0.047].ConclusionWe should pay more attention to elevated D-dimer levels not only as a sign of cancer-associated thrombosis but also the future occurrence of CTRCD.

ObjectivesThis study explored the health problems of inhabitants of small South Pacific Islands under the influence of climate change, focusing on three communities in the Solomon Islands.DesignCross-sectional study of the Solomon Islands’ populations.SettingA field survey was conducted in Taro Island, a small, urbanised island with a whole-community relocation plan; Manuopo community of Reef Islands, a small remote island on an atoll environment and Sasamungga, an intermediately urbanised community on a larger island. The Sasamungga community was used for comparison.ParticipantsEach community’s participants were recruited through local health authorities, and 113, 155 and 116 adults (aged 18+ years) from Taro, Manuopo and Sasamungga, respectively, participated voluntarily.MethodsEach participant’s body height, weight and body mass index were measured. A drop of blood was sampled for malaria testing; glycated haemoglobin and C reactive protein levels, measured from another drop of blood, were markers for diabetes and inflammation, respectively. The Primary Care Screening Questionnaire for Depression measured depressive mental states.Primary and secondary outcome measuresRegarding health status, the dependent variables—communicable diseases, non-communicable diseases and mental state—and independent variables—differences in communities and socioeconomic status—were measured through health check-ups and interviews of individual participants.ResultsTaro Island inhabitants had a higher risk of obesity (OR 1.13, 95% CI 1.02 to 1.27, p=0.0189), and Manuopo inhabitants had a higher risk of depression (1.25, 95% CI 1.08 to 1.44, p=0.0026) than Sasamungga inhabitants. Manuopo inhabitants recognised more serious problems of food security, livelihood, place to live and other aspects of daily living than other communities’ inhabitants.ConclusionsThe three small island communities’ observation identified different health problems: the urbanised community and remote community had a high risk of non-communicable diseases and mental disorders, respectively. These health problems should be monitored continuously during future climate-related changes.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary arterial remodeling. Clonal somatic mutations including JAK2V617F, the most frequent driver mutation among myeloproliferative neoplasms, have recently been identified in healthy individuals without hematological disorders. Here, we reveal that clonal hematopoiesis with JAK2V617F exacerbates PH and pulmonary arterial remodeling in mice. JAK2V617F-expressing neutrophils specifically accumulate in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines in chronic hypoxia-exposed JAK2V617F transgenic (JAK2V617F) mice, as well as recipient mice transplanted with JAK2V617F bone marrow cells. JAK2V617F progressively upregulates Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions. JAK2V617F-mediated STAT3 phosphorylation upregulates ALK1-Smad1/5/8 signaling. ALK1/2 inhibition completely prevents the development of PH in JAK2V617F mice. Finally, our prospective clinical study identified JAK2V617F-positive clonal hematopoiesis is more common in PH patients than in healthy subjects. These findings indicate that clonal hematopoiesis with JAK2V617F causally leads to PH development associated with ALK1 upregulation., Pulmonary hypertension is characterized by increased pulmonary arterial pressure, driven in part by inflammatory infiltrates. Here, the authors show that in mice, transgenic expression of mutant JAK2 leads to clonal hematopoiesis and lung accumulation of elastase- and cytokine-expressing neutrophils, and that the phenotype can be reversed by ALK1 inhibition.

Hereditary ATTR amyloid cardiomyopathy is defined as the intramyocardial deposition of amyloid fibrils derived from the mutation of transthyretin (TTR). A 51-year-old man was referred to our hospital for congestive heart failure. He and his family had no past history of heart diseases. Echocardiography showed remarkable left ventricular hypertrophy and reduced ejection fraction. Endomyocardial biopsy specimens presented positive staining of Congo-Red and transthyretin. A genetic test showed heterozygous V122I TTR gene mutation, which is very rare in Japan. We diagnosed him as with sporadic ATTR amyloidosis with mutation, and tafamidis was administered to stabilize TTR tetramer. Since the phenotype of ATTR amyloidosis varies depending on its penetration rate, it is crucial to always keep in mind the possibility of hereditary ATTR amyloidosis even in the case of amyloidosis with no clear family history.

Heart failure causes increased venous pressure, leading to liver dysfunction. The fibrosis-4 index is a simple index for liver fibrosis and has been reported to be useful for predicting prognosis in heart failure; however, its impact on patients with pulmonary hypertension due to left heart disease (PH-LHD) has not yet been fully elucidated.We enrolled consecutive 230 hospitalized patients who had been diagnosed as having PH-LHD. The fibrosis-4 index was calculated as follows: [aspartate transaminase (U/L) × age]/[alanine transaminase 1/2 (U/L) × platelet count (109/L) ]. We followed patients for all-cause mortality during the follow-up period (mean 1112 ± 822 days).The patients were divided into tertiles based on their fibrosis-4 index: the first tertile 0.335 to 1.381; the second tertile 1.391 to 2.311; and the third tertile 2.323 to 14.339. Compared with the first tertile, the third tertile had lower estimated glomerular filtration rates and hemoglobin levels. All-cause mortality was significantly higher in the third than in the first tertile. In a Cox proportional hazard model, the fibrosis-4 index was a predictor of all-cause mortality in PH-LHD patients (HR 1.212, 95% CI 1.099-1.337, P < 0.001).The fibrosis-4 index is associated with kidney function, anemia, and high mortality in PH-LHD patients.

Aging is not only a major risk factor for impaired collateral growth under ischemia but also shortens the telomere length, which is regulated by telomerase. We examined the role of telomerase activity during impaired collateral growth during aging in ischemic skeletal muscle. Unilateral hind limb ischemia was generated in old, young, and old mice chronically administered a telomerase activator. In old mice, blood flow recovery and capillary density development in ischemic hind limbs were reduced compared to those in young mice, and these changes were restored to equal levels by administration of TA-65, a telomerase activator. During the early phase of ischemic muscle changes in old mice, telomerase reverse transcriptase expression and telomerase activity were both low compared to those in young mice and old mice treated with TA-65. Levels of reactive oxygen species (ROS), DNA double-strand breaks, and expression of p53, p16, and Bax/Bcl-2 were all elevated in ischemic muscles of old mice compared to those in the muscles of young mice and old mice treated with TA-65 treatment; these factors were maintained at low levels equivalent to those seen in young mice during the experiment. Expression of HIF1α/vascular endothelial growth factor (VEGF) and PGC1α were decreased in old mice compared to those in young mice and old mice treated with TA-65. Collateral growth under ischemic conditions is impaired in aged animals due to low telomerase activity, increased ROS, resultant DNA damage, and expression of tumor suppressor and pro-apoptotic proteins. These data suggest that telomerase activation enhances collateral growth and rescues ischemic tissue in old individuals.

Objective Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease that leads to right-sided heart failure with electrocardiographic abnormalities. There are only a few reports about the effects of balloon pulmonary angioplasty for CTEPH on the electrocardiographic criteria of right ventricular hypertrophy. To determine the effect of balloon angioplasty on electrocardiography in patients with CTEPH. Methods We evaluated electrocardiograms in 19 patients (mean age, 64±10 years) who underwent balloon pulmonary angioplasty. Results We compared the hemodynamic parameters after balloon pulmonary angioplasty. The mean pulmonary artery pressure was decreased (p

The objective of this study was to develop mathematical equations for describing the change in marbling in Japanese Black steers using longitudinal measurements. Serial ultrasound measurements were taken at 14, 16, 20, and 26 months of age and analyzed using an image analysis software. The longitudinal marbling measurements from the ultrasound images and carcasses were fitted into a nonlinear logistic curve. Data used for the analysis consisted of 749 steers that converged in nonlinear curve fitting and showed reasonable estimated parameters of the logistic curves. The average predicted mature beef marbling score (BMS) and maturation rate were 6.26 and 0.353, respectively, and the average maturity levels at 24 months of age were 83.9%. The heritability estimates for the predicted maturity traits were moderate, indicating that these traits may have potential for genetic improvement. There was a negative relationship between the expected progeny differences between carcass BMS and maturity traits, suggesting that genetic improvement by carcass BMS may lead to the selection of bulls with late maturity for marbling. The results indicate that ultrasound and model building for marbling can be useful tools to correctly select candidate bulls with high marbling in the early fattening period.

The association of socio-economic-demographic (SED; e.g., income-related) factors with depression is widely confirmed in the literature. We conducted a hospital-based case–control study of 160 patients with psychiatrist-diagnosed clinical depression. The control group comprised 160 participants recruited from local communities. We used a questionnaire to collect SED data from all participants. We replaced missing values using multiple imputation analyses and further analyzed the pooled data of five imputations. We also recorded the results from the original analysis and each imputation. Univariate analyses showed income was associated with depression. Multiple logistic regression analyses revealed that, among all SED variables, high income (odds ratio = 2.088 [95% confidence interval = 1.178–3.700];p= 0.012), middle-level (completed junior or senior high school) education (1.688 [1.042–2.734];p= 0.033) and cohabitating with four or more family members (1.632 [1.025–2.597];p= 0.039) were significant predictors for the case group. We conclude that cash income is a determinant of depression in hospital outpatients in Indonesia. This study suggests health policy implications toward better hospital access and service for people with depression in middle- or low-income households, and recommends considering high income as correlated with a high risk of depression, owing to socio-cultural changes.

Background: Recently, a high-power short-duration (HP-SD) setting has been introduced in atrial fibrillation (AF) ablation. Ablation using this setting reduces collateral tissue damage by shortening the conductive heating phase compared to conventional setting. However, the lesion characteristics have not been rigorously evaluated during ablation procedure. We hypothesized that superior vena cava (SVC) potential could be affected by excessive transmural lesions in anterior-superior right pulmonary vein isolation (PVI), adjacent to posterior aspect of SVC. Therefore, we compared the produced potential delay in SVC between HP-SD and conventional settings. Methods and Results: The consecutive 42 patients (61±10 years, 32 men) who underwent PVI for drug refractory AF were analyzed. Before introduction of HP-SD setting to AF ablation in November 2018, 14 patients underwent right PVI with conventional setting with output of 20-30 W (Conventional group). In the remaining 28 patients after then, right PVI was performed using HP-SD setting with output of 45-50 W (HP-SD group). We compared total radiofrequency energy and mean contact force along the anterior superior right PVI line between the 2 groups. Moreover, the produced SVC potential delay was calculated after anterior superior right PVI and compared between the 2 groups. Total radiofrequency energy delivered (6138 J vs. 6139 J, P = 0.999) and the mean contact force (17.2 g vs. 20.2 g, P = 0.100) in the anterior superior right PV did not differ between the HP-SD and Conventional groups. However, the produced SVC potential conduction delay after anterior superior right PVI was significantly longer in Conventional group compared to HP-SD group (6.2 ms vs. 0.5 ms, P < 0.001). Conclusions: Our data suggest that HP-SD setting caused less collateral tissue damage than conventional setting during PVI. The significant produced SVC potential delay might be a surrogate marker of collateral tissue damage by conductive heating phase in PVI.

Background: Several studies have recently reported that transthyretin (ATTR) amyloidosis is present in patients with aortic stenosis (AS). We aimed to 1) examine the prevalence of ATTR amyloidosis in AS patients undergoing transcatheter aortic valve implantation (TAVI), 2) compare clinical characteristics between AS patients with and without ATTR, and 3) identify predictors of ATTR amyloidosis in AS patients. Methods and Results: We prospectively analyzed consecutive 32 patients with severe AS who underwent screening tests for ATTR in prior to TAVI. To detect ATTR, we performed cardiac technetium-99m pyrophosphate ( 99m Tc-PYP) scintigraphy in 24 patients and biopsies of fat tissue from the puncture site in 24 patients. Of 32 AS patients who were screened for ATTR, 6 (18.8%) patients were diagnosed as ATTR by cardiac 99m Tc-PYP scintigraphy (n=2) and fat biopsy (n=5). Compared with non-ATTR patients, ATTR patients presented higher levels of B-type natriuretic peptide (BNP, 242.3 vs. 1101.4 ng/ml, P=0.004), lower left ventricular ejection fraction (LVEF, 62.3 vs. 45.5%, P=0.002) and lower mean pressure gradient of AS (50.2 vs. 32.0 mmHg, P=0.016). In contrast, age, sex, STS score, clinical frailty scale, prevalence of chronic kidney disease and atrial fibrillation, and levels of hemoglobin, albumin, estimated glomerular filtration rate and troponin I were comparable between the two groups. Other echocardiographic parameters including interventricular septal wall thickness, posterior wall thickness and aortic valve area did not differ between the two groups. To detect ATTR among AS patients, receiver operating characteristic (ROC) analysis demonstrated that area under the curve of BNP, LVEF, and mean pressure gradient was 0.814, 0.766 and 0.846, respectively. Although TAVI was successfully completed in all patients, and there was no procedural complication in both groups, one of ATTR patients re-hospitalized due to decompensated heart failure 3 weeks after TAVI. Conclusion: In AS patients undergoing TAVI, especially in cases of low-flow low-gradient pattern and high BNP levels, screening of ATTR should be considered. In this population, cardiac 99m Tc-PYP scintigraphy and fat biopsy are useful to detect latent ATTR non-invasively.

Objective: To investigate the impact of hematopoietic JAK2V617F, which causes myeloproliferative neoplasms (MPNs), on the development of aortic aneurysm (AA). Approach and Results: We applied a bone marrow transplantation (BMT) strategy using the donor cells from Jak2 V617F transgenic (JAK2 V617F ) mice into the lethally irradiated apolipoprotein E-deficient mice. To induce the AA formation and progression, the recipient mice (BMT mice) were subjected to continuous angiotensin II infusion. Abdominal aortic diameter in JAK2 V617F -BMT mice was significantly enlarged compared to the control wild-type (WT)-BMT mice in response to angiotensin II. The incidence of abdominal AA was significantly higher in JAK2 V617F -BMT mice than in WT-BMT mice. Hematopoietic JAK2V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of CD68 + macrophages and Ly6B.2 + neutrophils and cytokine expressions such as Ccl6 and Tgfb1 were significantly increased in the abdominal aorta of JAK2 V617F -BMT mice accompanied by STAT3 activation. Bone marrow-derived macrophages carrying JAK2V617F showed elevations of both Mmp2 and Mmp9 mRNA expression. Finally, we found that 23% of MPN patients with JAK2 V617F mutation showed the presence of AA and increases in TGFB3 and IL-8 mRNA expression of the peripheral leukocytes. Conclusions: Hematopoietic JAK2V617F was involved in the development of AA through increases in the infiltration of inflammatory cells and MMP activation. Our findings provide a novel feature of vascular complication of AA in MPNs due to constitutive activation of the hematopoietic JAK-STAT pathway.

Introduction: American Society of Echocardiography and European Association of Cardiovascular Imaging have proposed the estimation of left ventricular (LV) filling pressures and grading LV diastolic function in patients with heart failure (HF). However, the associations of LV diastolic dysfunction (LVDD) grade with exercise capacity and prognosis have not been fully elucidated among HF patients with reduced LV ejection fraction (HFrEF, LVEF ≤40%), preserved EF (HFpEF, LVEF ≥50%) and mid-range EF (HFmrEF, LVEF 41% to 49%). We aimed to determine the differences in the associations of LVDD grade with parameters of cardiopulmonary exercise testing (CPX) and prognosis in patients with HFrEF, HFpEF and HFmrEF. Methods and Results: We analyzed data on 891 hospitalized patients with HF and sinus rhythm (SR), who had discharged alive and undergone CPX at stable condition in prior to discharge. Of 891 patients, 38.9% had HFrEF, 40.6% had HFpEF and 20.4% had HFmrEF. The HFrEF group had higher rates of adverse cardiac events, defined as cardiac death and re-hospitalizations for worsening HF, than HFpEF and HFmrEF groups. In HFrEF group, the patients with LVDD grade 1 had the highest peak oxygen uptake (peak VO 2 ), the lowest minute ventilation and carbon dioxide production (VE/VCO 2 slope), the highest oxygen uptake efficiency slope (OUES) and the lowest adverse cardiac event rates. However, there was no difference in CPX parameters and adverse cardiac event rates between patients with LVDD grade 2 and 3. In HFpEF group, the patients with LVDD grade 1 had the highest peak VO 2 , the lowest VE/VCO 2 slope and the highest OUES. In contrast, CPX parameters did not differ between patients with LVDD grade 2 and grade 3. Patients with LVDD grade 3 had the highest adverse cardiac event rates, followed by patients with grade 2 and 1. In HFmrEF group, the patients with LVDD grade 1 had the highest peak VO 2 , the lowest VE/VCO 2 slope and the highest OUES. Patients with grade 1 had the lowest adverse cardiac event rates. However, CPX parameters and adverse cardiac event rates did not differ between patients with grade 2 and 3. Conclusions: LVDD grade was associated with poor exercise capacity and adverse prognosis in patients with HF and SR, regardless of their LVEF.

Introduction: It has been reported that East Asian people have higher bleeding risks than Western people. The Patterns of non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) bleeding risk score was developed to estimate the bleeding risk after percutaneous coronary intervention (PCI). However, the utility of PARIS bleeding score for predicting long-term bleeding risks has not been validated in Japanese population. Methods: Consecutive 1061 patients who underwent PCI and survived to discharge were divided into three groups based on the category of PARIS bleeding risk score: low risk group (0-3 risk points), intermediate risk group (4-7 risk points) and high risk group (8-15 risk points), then we compared patient characteristics and followed bleeding events. Results: The numbers of patients at low, intermediate and high risk groups were 113 (10.7%), 420 (39.6%) and 528 (49.8%), respectively. Clinical characteristics for three groups were as follows: atrial fibrillation (low, intermediate and high risk groups; 8.2%, 8.9% and 21.6%, P &lt 0.001, respectively), peripheral artery disease (3.1%, 9.1% and 22.1%, P &lt 0.001), coronary multi-vessel disease (38.9%, 44.3% and 54.4%, P = 0.001), use of statin (97.3%, 89.6% and 71.7%, P &lt 0.001) and proton-pump inhibitors (69.1%, 72.5%, and 78.9%, P = 0.02). Among 1061 patients, a total of 74 bleeding events were occurred during the follow-up period (mean of 1742 days). In the Kaplan-Meier analysis, the cumulative incidence of bleeding events significantly increased from low risk group to intermediate and high risk group (P &lt 0.001). The risk score showed a significant prognostic value in predicting bleeding events (area under the receiver operating characteristic curve, 0.674; 95% confidence interval, 0.615-0.733). Conclusions: The PARIS bleeding risk score successfully stratified the long-term bleeding risk in patients with coronary artery disease after PCI in Japanese population.

Backgrounds: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and organic stenosis due to abnormal proliferation of pulmonary vascular cells. Endothelin (ET)-1 induces pulmonary vasoconstriction hyperplasia and plays a pivotal role in the pathogenesis of PAH. The germline mutations of activin receptor-like kinase (ACVRL)-1, a serine/threonine kinase and receptor for TGF-β, have been reported in idiopathic and hereditary PAH. However, the relationship between ET-1 and ACVRL-1 in the pathogenesis of PAH is largely unknown. Thus, we investigated the molecular mechanism of ACVRL-1 expression induced by ET-1 in human pulmonary arterial endothelial cells (hPAECs). Methods: ACVRL-1 expression levels were measured using Western blotting and quantitative real-time polymerase chain reaction. The promoter activity of ACVRL-1 was evaluated using dual luciferase assay. hPAECs were pretreated with pertussis toxin (PTX), cell-permeable C3 toxin (C3T) and Y27632 to inhibit Gi, RhoA and Rho kinase, respectively. GTP-RhoA, an active form of RhoA, was assessed using pull-down assay. Results: ET-1 increased mRNA and protein expression of ACVRL-1 in hPAECs (1.8±0.2 folds, P Conclusion: These data indicate that ET-1 increases ACVRL-1 expression both at transcriptional and post-transcriptional mechanisms via the Gi/RhoA/Rho kinase/Sp-1 axis in human PAECs.

Background: Previous studies suggest the association of metabolic disorder with pulmonary hypertension. Elevated pulmonary artery pressure induced by hypoxia in mice returns to normal when they are placed back in normoxia. In this study, we investigated the effect of high-fat diet (HFD) on pulmonary artery pressure and reverse remodeling of pulmonary artery in mouse model of hypoxia-induced pulmonary hypertension. Methods: We used the female C57/Bl6 mice at the age of 8 weeks. After exposed to hypoxia (10% oxygen for 4 weeks) for induction of pulmonary hypertension, mice were returned to normoxic condition and fed HFD or low-fat diet (LFD) for 12 weeks. Results: The body weight (BW), glucose, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C), but not triglyceride (TG) were significantly increased in HFD group (36.9±5.1 vs. 24.0±1.4 g [BW], P Conclusion: Our results suggest that metabolic disorder attenuates pulmonary artery reverse remodeling, at least in part, by suppressing apoptosis of pulmonary artery smooth muscle cells when hypoxia-induced pulmonary hypertension mice were returned to normoxia.

Background: The Patterns of non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) bleeding risk score has been proposed to predict the risk of bleeding events after percutaneous coronary intervention (PCI). However, the prognostic value of the PARIS bleeding risk score for long term all-cause and cardiac mortalities has not been evaluated. Therefore, we aimed to evaluate the predictive value of the PARIS bleeding risk score for all-cause and cardiac mortalities after PCI. Methods and Results: Consecutive 1061 patients, who had admitted to our hospital and performed or undergone PCI, were divided into 3 groups based on PARIS bleeding risk score: low (n = 113), intermediate (n = 420) and high risk groups (n = 528). We compared comorbidities and characteristics of patients among 3 groups. Furthermore, we prospectively followed up all-cause and cardiac mortalities. Clinical characteristics of 3 groups were as follows: mean age (low, intermediate and high risk groups; 56.5, 65.6 and 73.9 years, P < 0.001, respectively), prevalence of chronic kidney disease (2.7%, 24.2% and 67.8%, P < 0.001), atrial fibrillation (8.2%, 8.9% and 21.6%, P < 0.001) and peripheral artery disease (3.1%, 9.1% and 22.1%, P < 0.001). During the mean follow-up period of 1809 days, there were 205 deaths and 64 cardiac deaths. The Kaplan-Meier analysis revealed that both all-cause and cardiac mortalities were highest in high risk group among 3 groups (P < 0.001 and P < 0.001, respectively, Figure). In multivariable Cox proportional hazard analysis adjusted for confounding factors, PARIS bleeding score was an independent predictor of both all-cause and cardiac mortalities (adjusted hazard ratio 1.27 and 1.21 per 1 point increase, P < 0.001 and P = 0.004, respectively). Conclusion: The PARIS bleeding risk score showed significant prognostic values for all-cause and cardiac mortalities in patients after PCI.

Background: D-dimer is a sensitive biomarker for cancer-associated thrombosis, but little is known about its significance on cancer therapeutics-related cardiac dysfunction (CTRCD). Methods and Results: Consequtive 202 patients planned for cardiotoxic chemotherapy (anthracyclines, monoclonal antibodies, tyrosine kinase inhibitors, and proteasome inhibitors) were enrolled and followed up for 12 months. Cancer types were as follows: breast cancer (n=112), lymphoma (n=37), ovarian or uterine cancer (n=18), leukemia (n=13), multiple myeloma (n=6), bone cancer (n=4), and others (n=12). All patients underwent echocardiography and blood test at baseline, 3-month, 6-month, and 12-month. The patients were divided into 2 groups based on the value of D-dimer (>1.5 μg/ml or ≦1.5 μg/ml) at baseline before chemotherapy: High D-dimer group (n=52) and Low D-dimer group (n=150). At baseline, left ventricular ejection fraction (LVEF), left ventricular end-systolic volume index, and B-type natriuretic peptide levels were similar between two groups. Time-dependent decrease in LVEF was observed after chemotherapy in high D-dimer group (baseline, 66±5%; 3-month, 63±7%; 6-month, 62±7%; 12-month 62±6%; P=0.005, figure), but not in low D-dimer group. Time-dependent increase in troponin I was similarly observed after chemotherapy in both groups. The occurrence of CTRCD was higher in high D-dimer group than in low D-dimer group (11.5% vs. 4.0%, P=0.048). When we set the cut-off value of baseline D-dimer at 1.65 μg/ml from ROC analysis, sensitivity, specificity, and area under the curve to predict CTRCD were 50%, 77%, and 0.679, respectively. Multivariable logistic analysis revealed that baseline D-dimer was an independent factor to predict the decrease in LVEF more than 10% after cardiotoxic chemotherapy (odds ratio 1.210, 95% confidence interval [1.020-1.440], P=0.025). Conclusion: Baseline D-dimer is a pivotal parameter to predict CTRCD.

Rationale: Pulmonary hypertension (PH) is associated with hematological disorders by unclear multifactorial mechanisms. JAK2 V617F is the most frequent driver mutation among the myeloproliferative neoplasms and is recently identified in clonal hematopoiesis. However, the impact of clonal hematopoiesis on PH remains unknown. Objectives: To elucidate the mechanistic relevance of hematopoietic JAK2V617F in the development of PH. Methods: We applied experimental mouse models, mimicking hematological clinical scenarios using Jak2 V617F-transgenic (JAK2 V617F ) mice and recipient mice transplanted with JAK2 V617F bone marrow cells (JAK2 V617F recipients), exposed to chronic hypoxia to induce PH. The presence of JAK2 V617F was also examined prospectively in PH patients. Measurements and Main Results: Increases in right ventricular systolic pressure and right ventricular hypertrophy accompanied by pulmonary arterial structural remodeling after exposure to chronic hypoxia were significantly exacerbated in both JAK2 V617F mice which showed a myeloproliferative neoplasm-phenotype and JAK2 V617F recipients which modeled clonal hematopoiesis compared to corresponding controls. JAK2V617F-expressing neutrophils were specifically accumulated in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines. RNA sequencing identified progressive upregulation of Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions in the enrichment of JAK-STAT-related molecules by JAK2V617F. JAK2V617F-mediated STAT3 phosphorylation upregulated ALK1-Smad1/5/8 signaling. Strikingly, ALK1 inhibition completely rescued the development of PH in JAK2 V617F mice. Furthermore, clonal hematopoiesis with JAK2 V617F was significantly more common in PH patients than in healthy subjects. Conclusions: Our study reveals clonal hematopoiesis with JAK2V617F as a crucial factor that causally leads to PH through ALK1.

Background: It has been known that East Asian people, including Japanese, has a high bleeding risk (HBR) than Western. Therefore, risk stratification is important to detect HBR patients among patients who underwent percutaneous coronary intervention (PCI). The aim of the present study was to investigate the association between serum albumin level and bleeding events in patients who underwent PCI. Methods and Results: Consecutive 1027 patients who underwent PCI and had been discharged from our institution were enrolled. We divided the patients into three groups based on serum albumin levels at discharge: the first tertile (≤3.7 g/dL, n=358), second tertile (3.8-4.1 g/dL, n=308) and third tertile (≥4.2 g/dL, n=361). Clinical characteristics of three groups were as follows: mean age (the first, second and third tertile; 72.9, 69.3 and 63.4 years, P2 , P Conclusion: In patients who underwent PCI, low serum albumin level is independently associated with long-term bleeding events.

Background DNA damage likely contributes to the pathogenesis and progression of atherosclerosis. Chemotherapy, radiotherapy and some DNA damage response (DDR) syndromes are known to increase atherosclerosis. However, causative links between DNA damage and atherosclerosis are yet to be established. Purpose The aim of this study was to investigate the role of impaired DDR in atherosclerosis. Methods and results Ku80, a DNA repair protein, -deficient apolipoprotein E knockout mice (Ku80+/− ApoE−/−) and ApoE−/m- mice were fed on high-fat diet for 4 weeks, and then oil red O staining was performed on their isolated aortas. Plaque area was significantly increased in Ku80+/− ApoE−/− mice. Immunohistochemical analysis of lesions from Ku80+/− ApoE−/− mice revealed enhanced accumulation of DNA double-strand breaks (DSBs). Similar results were obtained from Ku80+/− ApoE−/− mice fed on high-fat diet for 2 weeks which was considered as the early stages of atherosclerosis. mRNA levels of inflammatory cytokines such as IL-6 and MCP-1 in the aorta were significantly elevated in Ku80+/− ApoE−/− mice compared with those of ApoE−/− mice. To investigate whether impaired DDR is associated with the increased expression of inflammatory cytokines, vascular smooth muscle cells were isolated from Ku80 WT and Ku80+/− mice and subjected to quantitative RT-PCR analysis. mRNA levels of IL-6 and MCP-1 were significantly elevated in Ku80+/− cells. In addition, IκBα protein expression was significantly decreased in Ku80+/− cells, which suggested enhanced NF-κB activation in those cells. Immunofluorescent analysis revealed accumulation of DSBs and persistent DDR in Ku80+/− cells. In addition, elevated p16 mRNA level and senescence-associated β-gal activity were observed in Ku80+/− cells. Conclusion These results suggested that impaired DDR promoted atherosclerosis partly through cellular senescence and enhanced proinflammatory activation. Therefore, therapies targeting enhancing DDR may be beneficial in the prevention of DNA damage-induced atherosclerosis. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): KAKENHI

Background Soluble guanyl cyclase (sGC) is a receptor for nitric oxide (NO) and plays an important role in vascular tonus. sGC stimulant is a therapeutic agent for pulmonary hypertension and an advantage of sGC stimulant over phosphodiesterase (PDE)-5 inhibitors is that sGC stimulant exerts its effect even when NO production is reduced. NO derived from vascular endothelial cells is immediately absorbed by hemoglobin (Hb), which leads to the production of methemoglobin (Met-Hb) when oxidized. Previous report has shown that the therapeutic effect of PDE-5 inhibitors was associated with levels of Met-Hb. Purpose In this study, we examined the relationship between the effect of riociguat and levels of Met-Hb in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods The study population comprised 18 patients with CTEPH. Mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) were assessed before and after administration of riociguat, and changes in mPAP and PVR were defined as ΔmPAP and ΔPVR, respectively. Since the level of Met-Hb was obtained as the percentage of Hb (FMet-Hb), the amount of Met-Hb was calculated by following formula: Met-Hb (mg/dL) = Hb (g/dL) × FMet-Hb (%) × 10. Results The amount of Met-Hb value before administration of riociguat was significantly correlated with the degree of improvement in mPAP and PVR after administration of riocigat (R=−0.502, P Conclusion Our findings suggest that the level of Met-Hb before treatment may predict the therapeutic effect of sGC stimulants in patients with CTEPH. Funding Acknowledgement Type of funding source: None

Objective The relationship between changes in the nutritional status after cardiac resynchronization therapy (CRT) and the prognosis has not been fully elucidated. We aimed to evaluate the changes in the nutritional status as assessed by the prognostic nutritional index (PNI) and their associations with the improvement in the cardiac function and subsequent clinical outcomes. Methods The study population consisted of 119 patients with a CRT-device. They were divided into 2 groups, based on whether their PNI had increased at 6 months after CRT-device implantation (positive ΔPNI group, n=73) or not (negative ΔPNI group, n=46). The left ventricular (LV) end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were measured before and six months after CRT-device implantation. We compared the changes in the cardiac function and prevalence of adverse events (re-hospitalization due to worsening heart failure or all cause death) between the two groups. Results In the positive ΔPNI group, the LVEDV (186±93 mL vs. 149±71 mL, p

In this work, individual radiosensitivity was evaluated using DNA damage response and chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) for the prediction of acute toxicities of chemoradiotherapy (CRT) in esophageal cancer patients. Eighteen patients with esophageal cancer were enrolled in this prospective study. Prescribed doses were 60 Gy in 11 patients and 50 Gy in seven patients. Patients received 2 Gy radiotherapy five days a week. PBLs were obtained during treatment just before and 15 min after 2 Gy radiation therapy on the days when the cumulative dose reached 2, 20, 40 Gy and 50 or 60 Gy. PBLs were also obtained four weeks and six months after radiotherapy in all and 13 patients, respectively. Dicentric and ring chromosomes in PBLs were counted to evaluate the number of CAs. Gamma-H2AX foci per cell were scored to assess DNA double-strand breaks. We analyzed the association between these factors and adverse events. The number of γ-H2AX foci before radiotherapy showed no significant increase during CRT, while their increment was significantly reduced with the accumulation of radiation dose. The mean number of CAs increased during CRT up to 1.04 per metaphase, and gradually decreased to approximately 60% six months after CRT. Five patients showed grade 3 toxicities during or after CRT (overreactors: OR), while 13 had grade 2 or less toxicities (non-overreactors: NOR). The number of CAs was significantly higher in the OR group than in the NOR group at a cumulative dose of 20 Gy (mean value: 0.63 vs. 0.34, P = 0.02), 40 Gy (mean value: 0.90 vs. 0.52, P = 0.04), and the final day of radiotherapy (mean value: 1.49 vs. 0.84, P = 0.005). These findings suggest that number of CAs could be an index for predicting acute toxicities of CRT for esophageal cancer.

The performance of a direct electron detector using silicon-on-insulator (SOI) technology in a low-voltage transmission electron microscope (LVTEM) is evaluated. The modulation transfer function and detective quantum efficiency of the detector are measured under backside illumination. The SOI-type detector is demonstrated to have high sensitivity and high efficiency for the direct detection of low-energy electrons. The detector is thus considered suitable for low-dose imaging in an LVTEM.

Background: Red blood cell distribution width (RDW) is associated with prognosis in widespread cardiovascular fields, but little is known about relationship with the onset of cancer therapeutics-related cardiac dysfunction (CTRCD). Objectives: The purpose of this study was to assess whether RDW could predict the onset of CTRCD by anthracycline. Methods: Consequential 202 cancer patients planed for anthracycline treatment were enrolled and followed up for 12 months. The patients were divided into 2 groups based on the median value of baseline RDW before chemotherapy [low RDW group, n = 98, 13.0 [12.6-13.2]; high RDW group, n = 104, 14.9 [13.9-17.0]]. Cardiac function was assessed serially by echocardiography at baseline (before chemotherapy), as well as at 3, 6, and 12 months after chemotherapy with anthracycline. Results: Baseline left ventricular end systolic volume index and ejection fraction (EF) were similar between two groups. After chemotherapy, EF decreased at 3- and 6-month in the high RDW group [baseline, 64.5% [61.9-68.9%]; 3-month, 62.6% [60.4-66.9%]; 6-month, 63.9% [60.0-67.9%]; 12-month, 64.7% [60.8-67.0%], P = 0.04], but no change was observed in low RDW group. The occurrence of CTRCD was higher in high RDW group than in low RDW group (11.5 vs. 2.0%, P = 0.008). When we set the cut-off value of RDW at 13.8, sensitivity and specificity to predict CTRCD were 84.6 and 62.0%, respectively. Multivariable logistic regression analysis revealed that baseline RDW value was an independent predictor of the development of CTRCD [odds ratio 1.390, 95% CI [1.09-1.78], P = 0.008]. The value of net reclassification index (NRI) and integrated discrimination improvement (IDI) for detecting CTRCD reached statistical significance when baseline RDW value was added to the regression model including known risk factors such as cumulative anthracycline dose, EF, albumin, and the presence of hypertension; 0.9252 (95%CI 0.4103-1.4402, P < 0.001) for NRI and 0.1125 (95%CI 0.0078-0.2171, P = 0.035) for IDI. Conclusions: Baseline RDW is a novel parameter to predict anthracycline-induced CTRCD.

Background The prognostic impact of benzodiazepines has been unclear in patients with heart failure (HF). Methods and Results This was a historical observational cohort study. A total of 826 patients who had been hospitalized for HF and were being treated for insomnia with either benzodiazepines or Z‐drugs (zolpidem, zopiclone, or eszopiclone), were enrolled and divided on the basis of their hypnotics: benzodiazepine group (n=488 [59.1%]) and Z group (n=338 [40.9%]). We compared the patient characteristics and postdischarge prognosis between the groups. The primary end points were rehospitalization for HF and cardiac death. The benzodiazepine group was older (age, 72.0 versus 69.0 years; P =0.010), had a higher prevalence of depression (17.4% versus 8.9%; P P =0.001). In the laboratory data, the benzodiazepine group demonstrated lower levels of hemoglobin (12.3 versus 13.0 g/ dL ; P =0.001), sodium (139.0 versus 140.0 mE q/L; P =0.018), and albumin (3.7 versus 3.9 g/ dL ; P =0.003). Kaplan‐Meier analysis showed that both end points were higher in the benzodiazepine group (rehospitalization for HF , log‐rank P =0.001; cardiac death, log‐rank P =0.043). Multiple Cox proportional hazard analysis revealed that the use of benzodiazepines was an independent predictor of rehospitalization for HF (hazard ratio, 1.530; 95% CI, 1.025–2.284; P =0.038). Furthermore, rehospitalization for HF was higher in the benzodiazepine group after propensity score matching (log‐rank P =0.036). Conclusions Benzodiazepine is associated with higher risk of rehospitalization for HF compared with Z‐drugs in patients with HF .

Background Cardiac amyloidosis (CA) is characterized by left ventricular hypertrophy (LVH) and autonomic nervous imbalance due to amyloid infiltration. However, autonomic dysfunction is often seen in heart failure (HF) with LVH from other etiologies. We aimed to characterize autonomic dysfunction in CA from other etiologies of LVH. Methods Fifty‐five HF patients with LVH (35 males, mean age 65 ± 16 years) were enrolled. LVH was defined as left ventricular mass index measured by echocardiography >95 g/m2 in women and 115 g/m2 in men. The etiology was as follows: amyloid light chain (AL)‐CA, n = 14; hypertrophic cardiomyopathy, n = 21; and aortic stenosis (AS), n = 20. With the patient in a clinically stable condition, heart rate variability (HRV) and heart rate turbulence (HRT), which reflect autonomic dysfunction, were measured using Holter monitoring and compared among the three groups. Results Brain natriuretic peptide levels, LVH severity, left ventricular ejection fraction, and tissue Doppler index E/e′ did not differ among the three groups. However, severe abnormalities of HRV and HRT were obtained in AL‐CA. In the ROC analysis to identify AL‐CA in HF with LVH, the best cutoff value for standard deviation of all R‐R intervals, standard deviation of the 5‐min mean R‐R intervals, turbulence onset, and turbulence slope were 68.5 ms (AUC: 0.865), 58.5 ms (AUC: 0.834), 0.25% (AUC: 0.813), and 1.00 ms/RR (AUC 0.736), respectively. Conclusion Autonomic dysfunction is a hallmark of AL‐CA, and its noninvasive assessment by Holter monitoring may be a useful tool for differential diagnosis of HF with LVH.

Several studies have shown that neural remodeling in stellate ganglia (SG) is induced by myocardial infarction (MI). It remains unclear whether neural remodeling after MI is limited in SG within the sympathetic nervous system (SNS). MI was induced in a rat model by ligation of the left anterior descending artery. Neural remodeling in the intermediolateral nucleus (IML) and SG was assessed by immunohistochemistry 2 weeks after MI. The mRNA and protein expressions of brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase receptor (TrkB) and extracellular signal-regulated kinase (ERK) were measured by quantitative RT-PCR, immunohistochemistry and Western blotting 1 week after MI. The neuronal size and axonal density of IML were increased after MI compared to sham. The density of growth-associated protein-43, a protein upregulated in axons undergoing nerve sprouting, was increased after MI compared to sham. The fluorescence intensity of BDNF and TrkB in IML were significantly higher in the MI group than in the sham group. In addition, mRNA expressions of BDNF and TrkB in the spinal cord at the Th2 level was increased after MI. Finally, the percentage of phospho-ERK-immunoreactive cells in IML was significantly higher in the MI group than in the sham group. In conclusion, neural remodeling after MI in IML is associated with the activation of BDNF-TrkB axis. Morphological remodeling throughout the SNS may be involved in sustained activation of sympathetic tone after MI.

Orbital angular momentum (OAM) of electrons in free space must be omnipresent, but unfortunately we lack efficient equipment and techniques to measure the OAM state of an electron beam. This work demonstrates that a nanofabricated diffraction grating can be used as a device to address this problem. The authors present a protocol for obtaining an electron beam's OAM spectrum, and experimentally demonstrate how this approach can be used in a variety of applications, including those with magnetic materials. The results will have an impact on a great range of studies of electron OAM, and of other quantum waves, too.

Background Patients with some mutations in the lamin A/C (LMNA) gene are characterized by the presence of dilated cardiomyopathy (DCM), conduction abnormalities, ventricular tachyarrhythmias (VT), and sudden cardiac death (SCD). Various clinical features have been observed among patients who have the same LMNA mutation. Here, we show a family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, and a family history of conduction disorder, DCM, VT, and SCD. Case presentation A proband (female) with atrial fibrillation and bradycardia was implanted with a pacemaker in her fifties. Twenty years later, she experienced a loss of consciousness due to polymorphic VT. She had a serious family history; her mother and elder sister died suddenly in their fifties and sixties, respectively, and her nephew and son were diagnosed as having DCM. Genetic screening of the proband, her son, and nephew identified a nonsense mutation (c.475G > T, p.E159*) in the LMNA gene. Although the proband’s left ventricular ejection fraction remained relatively preserved, her son and nephew’s left ventricular ejection fraction were reduced, resulting in cardiac resynchronization therapy by implantation of a defibrillator. Conclusions In this family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, DCM, SCD, and malignant VT occurred. Clinical manifestation of various atrial and ventricular arrhythmias and heart failure with reduced ejection fraction occurred in an age-dependent manner in all family members who had the nonsense mutation. It appears highly likely that the E159* LMNA mutation is related to various cardiac problems in the family of the current report.

Pulmonary arterial hypertension is a fatal disease caused by pulmonary arterial vasoconstriction and organic stenosis due to the proliferation of pulmonary smooth muscle cells and endothelial cells. Endothelial dysfunction, including impaired nitric oxide (NO) bioavailability, plays a crucial role in the pathogenesis of pulmonary hypertension, and endothelial nitric oxide synthase (eNOS) is an important modulator of pulmonary vasodilatation. Although senescence marker protein (SMP) 30 is known as an anti-aging protein, the role of SMP30 in pulmonary vessels is still unclear. In this study, we examined the role of SMP30 in pulmonary vasculature using SMP30-deficient mice.We used female SMP30-deficient mice and wild-type littermate (WT) mice at the age of 12 to 18 weeks. The WT and SMP30-deficient mice were exposed to normoxia or hypoxia (10% oxygen for 4 weeks). In normoxia, the right ventricular systolic pressure (RVSP) was not different between the WT and SMP30-deficient mice, but in hypoxia, the RVSP was significantly higher in the SMP30-deficient mice compared to the WT mice (P < 0.05). The hypoxia-induced increases in right ventricular hypertrophy and medial smooth muscle area of the pulmonary artery were comparable between the WT and the SMP30-deficient mice. Western blotting showed that eNOS phosphorylation in lung tissue was reduced in the SMP30-deficient mice compared to the WT mice in normoxia. However, in hypoxic conditions, eNOS phosphorylation was reduced in both the WT and SMP30-deficient mice with no differences in Akt phosphorylation.Our study demonstrated that SMP30 is involved in the development of hypoxia-induced pulmonary hypertension by impairment of eNOS activity.

Exhaled acetone concentration is one of the expected compounds to be a breath biomarker in heart failure. However, it has not been clarified how exhaled acetone concentration changes in clinical course of heart failure.To investigate whether exhaled acetone concentration changes after treatment in acute decompensated heart failure (ADHF).This study included 19 patients with ADHF (ADHF group) and eight patients with stable heart failure (control group). Exhaled acetone was collected from these patients, and the concentration was measured with gas chromatography.The ADHF group had higher heart rates (P = 0.046), higher New York Heart Association class (P < 0.001), higher levels of brain natriuretic peptide (P = 0.026), blood total ketone bodies (P = 0.015), and exhaled acetone concentration (P < 0.001), compared with the control group. In ADHF group, exhaled acetone concentration significantly decreased after treatment (median: 2.40 versus 0.92 ppm, P < 0.001). However, in the control group, exhaled acetone concentration did not significantly change (median: 0.73 versus 0.49 ppm, P = 0.141).In these preliminary findings, exhaled acetone concentration in patients with ADHF drastically decreased by treatment. Serial exhaled acetone measurement might be useful to evaluate the course of ADHF.

BACKGROUND Heart failure (HF) patients have a higher risk of recurrent HF and cardiac death, and electrical remodeling is considered to be an important factor for HF progression. The present study aimed to validate the utility of electrocardiogram and Holter monitoring for the risk stratification of HF patients. METHODS Our study comprised 215 patients (144 males, mean age 62 years) who had been hospitalized due to acute decompensated HF. Electrocardiogram (QRS duration and QTc interval) and 24-hour Holter monitoring (heart rate variability, heart rate turbulence, and T-wave alternans [TWA]) were performed in stable condition before discharge. The clinical characteristics and outcomes were then investigated. RESULTS During a median follow-up period of 2.7 years, there were 83 (38.6%) cardiac events (rehospitalization due to worsening HF [n = 51] or cardiac death [n = 32]). The patients with cardiac events had a lower turbulence slope (TS) and higher TWA compared to those without cardiac events (TS, 3.0 ± 5.5 ms/RR vs. 5.3 ± 5.6 ms/RR, P = 0.001; TWA, 66.1 ± 19.6 μV vs. 54.7 ± 15.1 μV, P

Pulmonary hypertension (PH) causes right ventricular dysfunction and central venous congestion, and may lead to congestive hepatopathy. The serum 7S domain of collagen type IV (P4NP 7S) is an established marker of liver fibrosis in chronic liver disease. We aimed to determine whether P4NP 7S is related to hemodynamic parameters, and assessed the potential values of P4NP 7S to predict mortality.Consecutive 76 pre-capillary PH patients were divided into tertiles based on their serum P4NP 7S levels. We compared right-heart catheterization, echocardiographic findings, and mortality among the tertiles, and compared P4NP 7S with other known biomarkers of mortality.Cardiac index, mean pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular fractional area change did not differ among the three groups. In contrast, compared to 1st and 2nd tertiles, the 3rd tertile had higher levels of right atrial pressure, right atrial area, and right ventricular area (P0.05, respectively). In the Kaplan-Meier analysis, mortality progressively increased from the 1st to 2nd and 3rd tertiles (log-rank, P=0.002). In the Cox proportional hazard analysis, P4NP 7S was a predictor of mortality. ROC analysis demonstrated that a P4NP 7S concentration of 4.75ng/ml predicted mortality (AUC 0.85, 95% CI 0.75-0.94; P0.001), and that the prognostic value of P4NP 7S was comparable or superior to that of other biomarkers (total bilirubin, creatinine, uric acid, C-reactive protein, B-type natriuretic peptide, and troponin I).Serum P4NP 7S is associated with higher central venous pressure, right-sided volume overload, and mortality in PH patients.

Aims Sleep-disordered breathing (SDB) is associated with arterial stiffness, which may be one of the factors that lead to heart failure (HF). We examined the relationship between pulse wave velocity (PWV) and SDB in patients who have HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Methods and results We measured the apnoea–hypopnoea index (AHI) by polysomnography, echocardiographic parameters, and PWV in 221 HF patients. Age, blood pressure, and PWV were higher in HFpEF (ejection fraction > 50%, n = 70) patients than in HFrEF (ejection fraction 30 times/h, n = 85). Although blood pressure and echocardiographic parameters did not differ among the three groups, PWV was significantly higher in the severe SDB group than in the none-to-mild and moderate SDB groups (P = 0.002). When the HFrEF and HFpEF patients were analysed separately, PWV was significantly higher in the severe SDB group than in the none-to-mild and moderate SDB groups in patients with HFpEF (P = 0.002), but not in those with HFrEF (P = 0.068). In the multiple regression analysis to determine PWV, the presence of severe SDB was found to be an independent predictor of high PWV in HFpEF (β = 0.234, P = 0.005), but not in HFrEF patients. Conclusions Severe SDB is associated with elevated arterial stiffness and may be related to the pathophysiology of HF, especially in HFpEF patients.