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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 mortality, cardiac mortality and hospitalization due to heart failure has not yet been evaluated. Therefore, the aim of the present study was to evaluate the prognostic value of the PARIS bleeding risk score for all-cause and cardiac mortalities and hospitalization due to heart failure after PCI. Consecutive 1061 patients who had undergone PCI were divided into 3 groups based on the PARIS bleeding risk score; low (n = 112), intermediate (n = 419) and high-risk groups (n = 530). We prospectively followed up the 3 groups for all-cause and cardiac mortalities and hospitalization due to heart failure. Kaplan-Meier analysis revealed that all of the outcomes were highest in the high-risk group among the 3 groups (P0.001, P0.001 and P0.001 respectively). Multivariable Cox proportional hazard analysis, adjusted for confounding factors, revealed that all-cause mortality of the intermediate or high-risk groups was higher than those of the low-risk group (adjusted hazard ratio 6.06 and 12.50, P = 0.013 and P0.001, respectively). The PARIS bleeding risk score is a significant indicator of prognosis for all-cause mortality in patients after PCI.

Cigarette smoking is a major risk factor for atherosclerosis. We previously reported that DNA damage was accumulated in atherosclerotic plaque, and was increased in human mononuclear cells by smoking. As vascular endothelial cells are known to modulate inflammation, we investigated the mechanism by which smoking activates innate immunity in endothelial cells focusing on DNA damage. Furthermore, we sought to characterize the plasma level of cell-free DNA (cfDNA), a result of mitochondrial and/or genomic DNA damage, as a biomarker for atherosclerosis. Cigarette smoke extract (CSE) increased DNA damage in the nucleus and mitochondria in human endothelial cells. Mitochondrial damage induced minority mitochondrial outer membrane permeabilization, which was insufficient for cell death but instead led to nuclear DNA damage. DNA fragments, derived from the nucleus and mitochondria, were accumulated in the cytosol, and caused a persistent increase in IL-6 mRNA expression via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. cfDNA, quantified with quantitative PCR in culture medium was increased by CSE. Consistent with in vitro results, plasma mitochondrial cfDNA (mt-cfDNA) and nuclear cfDNA (n-cfDNA) were increased in young healthy smokers compared with age-matched nonsmokers. Additionally, both mt-cfDNA and n-cfDNA were significantly increased in patients with atherosclerosis compared with the normal controls. Our multivariate analysis revealed that only mt-cfDNA predicted the risk of atherosclerosis. In conclusion, accumulated cytosolic DNA caused by cigarette smoke and the resultant activation of the cGAS-STING pathway may be a mechanism of atherosclerosis development. The plasma level of mt-cfDNA, possibly as a result of DNA damage, may be a useful biomarker for atherosclerosis.

Atherosclerosis is a cause of coronary artery disease, abdominal aortic aneurysm, and stroke. The pathogenesis underlying atherosclerosis is complex but it is clear that inflammation plays a pivotal role. Inflammation in atherosclerosis is triggered by the recognition of intracellular contents released from damaged cells by pattern recognition receptors, and is therefore sterile and chronic. Because the DNA of these cells is damaged, cellular senescence is also involved in this inflammation. Here, we will discuss the emerging evidence of a relationship between DNA damage and inflammation in the pathogenesis of atherosclerosis, with a focus on intracellular events and cell fates that arise following DNA damage. Recent evidence will lead us to potential therapeutic targets and allow us to explore potential preventative and therapeutic strategies.

A next-generation sequencing (NGS) study identified a very high viral load of Torquetenovirus (TTV) in KD patients. We aimed to evaluate the feasibility of a newly developed quantitative species-specific TTV-PCR (ssTTV-PCR) method to identify the etiology of KD. We applied ssTTV-PCR to samples collected from 11 KD patients and 22 matched control subjects who participated in our previous prospective study. We used the NGS dataset from the previous study to validate ssTTV-PCR. The TTV loads in whole blood and nasopharyngeal aspirates correlated highly (Spearman’s R = 0.8931, p < 0.0001, n = 33), supporting the validity of ssTTV-PCR. The ssTTV-PCR and NGS results were largely consistent. However, inconsistencies occurred when ssTTV-PCR was more sensitive than NGS, when the PCR primer sequences mismatched the viral sequences in the participants, and when the NGS quality score was low. Interpretation of NGS requires complex procedures. ssTTV-PCR is more sensitive than NGS but may fail to detect a fast-evolving TTV species. It would be prudent to update primer sets using NGS data. With this precaution, ssTTV-PCR can be used reliably in a future large-scale etiological study for KD.

Almost 40% of medical radiation exposure is related to cardiac imaging or intervention. However, the biological effects of low-dose radiation from medical imaging remain largely unknown. This study aimed to evaluate the effects of ionized radiation from cardiac catheterization on genomic DNA integrity and inflammatory cytokines in patients and operators.Peripheral mononuclear cells (MNCs) were isolated from patients (n = 51) and operators (n = 35) before and after coronary angiography and/or percutaneous coronary intervention. The expression of γH2AX, a marker for DNA double-strand breaks, was measured by immunofluorescence. Dicentric chromosomes (DICs), a form of chromosome aberrations, were assayed using a fluorescent in situ hybridization technique.In the patient MNCs, the numbers of γH2AX foci and DICs increased after cardiac catheterization by 4.5 ± 9.4-fold and 71 ± 122%, respectively (P0.05 for both). The mRNA expressions of interleukin (IL)-1α, IL-1β, leukemia inhibitory factor, and caspase-1 were significantly increased by radiation exposure from cardiac catheterization. The increase in IL-1β was significantly correlated with that of γH2AX, but not with the dose area product. In the operators, neither γH2AX foci nor the DIC level was changed, but IL-1β mRNA was significantly increased. The protein expression of IκBα was significantly decreased in both groups.DNA damage was increased in the MNCs of patients, but not of operators, who underwent cardiac catheterization. Inflammatory cytokines were increased in both the patients and operators, presumably through NF-κB activation. Further efforts to reduce radiation exposure from cardiac catheterization are necessary for both patients and operators.

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.

Although recent advances in cancer treatment improve cancer prognosis, cancer therapeutics-related cardiovascular dysfunction (CTRCD) significantly contributes to the global burden of cardiovascular disease. CTRCD causes two crucial issues: first, premature treatment interruption or discontinuation of chemotherapy; second, the development of congestive heart failure during and after cancer treatment. Thus, early detection and prompt treatment of CTRCD may improve the prognosis in cancer patients. This review covers representative anticancer drugs, including anthracyclines, human epidermal growth factor 2 inhibitors, tyrosine kinase inhibitors, proteasome inhibitors, and immune checkpoint inhibitors. We focus on the molecular mechanisms of CTRCD and various approaches to diagnosis, prevention, monitoring, and treatment.

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 (

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.

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.

Background: Cancer therapeutics-related cardiac dysfunction (CTRCD) is a concerning problem in anthracycline-containing chemotherapy. However, the impact of CTRCD on cancer-related mortality is remained to be elucidated. Methods: Consecutive 174 patients planned for anthracycline-containing chemotherapy were enrolled. Echocardiography and blood test were performed at baseline, 3 months, 6 months, 12 months after starting chemotherapy, and after that every 3 months until cardiotoxic chemotherapy was completed. Results: Of 174 patients, CTRCD was developed in 16 patients (CTRCD group, median onset was 8 months), and the other patients (no-CTRCD group) showed normal left ventricular ejection fraction (LVEF). CTRCD group showed higher levels of peak troponin I (0.05 [0.04-0.16] ng/ml vs. 0.02 [0.02-0.04] ng/ml, P Conclusion: The development of CTRCD was associated with high risk of cancer death, but not with cardiac death. Cardioprotective treatment and careful cancer monitoring are required to the patients with CTRCD.

Introduction: Parameters derived from cardiopulmonary exercise testing (CPX) including peak oxygen consumption (VO 2 ) are important prognostic factors in patients with chronic heart failure (CHF). However, all patients with CHF cannot undergo CPX because of such as exercise intolerance. On the other hands, resting parameters derived from respiratory gas analyzer including resting energy expenditure (REE) could be easily measured and clinical significance of these parameters had not been fully elucidated in patients with CHF. We aimed to determine the prognostic impact of REE in patients with CHF. Methods: A total of 1185 consecutive CHF patients underwent CPX were enrolled. The subjects of this study were divided into two groups according to median REE and we compered the clinical characteristics between two groups. Also, we examined the value of REE (Weir’ formula: 3.941resting VO 2 +1.106resting VCO 2 ) to predict cardiac mortality in CHF patients. Results: In all subjects, 966 were males, median age was 63 years. Median resting VO 2 was 236 ml/min, median resting VCO 2 was 222 ml/min and median REE was 1178 kcal/day. Patients with low REE (2 and lower resting VCO 2 and lower peak VO 2 than those with high REE ( > 1178 kcal/day). But left ventricular ejection fraction was similar between two groups. Patients with low REE had significantly higher rates of cardiac death, all cause death and composite cardiac events (cardiac death and re-hospitalization due to worsening heart failure) than those with high REE. Furthermore, REE was the independent predictor of cardiac death, all-cause death and composite cardiac events in the Cox proportional hazard analysis after adjusting for cofounding variables including peak VO 2 . Conclusions: REE as well as peak VO 2 is important predictor of cardiac mortality in patients with CHF.

Objective: Smoking is a well-known risk factor for atherosclerosis, yet the mechanism by which smoking causes atherosclerosis remains unclear. It has been reported that inflammation and DNA damage are involved in the formation and development of atherosclerosis. We have previously reported that nuclear DNA damage was increased in peripheral mononuclear cells of smokers compared to those of non-smokers, and that DNA damage was accumulated in atherosclerotic lesions. In this study, to clarify the mechanism by which smoking induces inflammation in vascular endothelial cells, we investigated the effect of cigarette smoke extract (CSE) on both nuclear and mitochondrial DNA damage and the subsequent cellular response in human umbilical vein endothelial cells (HUVEC). Methods and Results: CSE increased double-strand breaks in HUVEC. Notably, this increase was detected relatively late (after 3 days of CSE exposure) compared to other genotoxic agents. CSE also increased oxidative DNA damage both in the nucleus and mitochondria and induced mitochondrial dysfunction. Mitochondrial dysfunction decreased cytosolic protein levels of ICAD, an inhibitor of caspase-activated DNase (CAD), which causes nuclear DNA fragmentation, and increased CAD in the nucleus, suggesting that this is one of the mechanisms of nuclear DNA double-strand breaks. In addition, continuous stimulation by CSE induced the accumulation of cytosolic DNA. Interestingly, real-time PCR analysis revealed that the accumulated DNA in the cytosol was derived not only from the nucleus but also from mitochondria. We further examined whether DNA accumulated in the cytosol activated cytosolic DNA-sensing pathways. The production of cGAMP, a second messenger in cGAS (a DNA-sensing receptor) signaling, was increased by CSE. We also found that the mRNA expression of IL-6 was increased by CSE, and that the increase was suppressed by si-cGAS. Conclusions: This study showed that continuous exposure to CSE induces not only nuclear but also mitochondrial DNA damage, which leads to cytosolic DNA accumulation, and evokes chronic inflammation via the cGAS-STING pathway.

Background: It has been reported that nutritional risk index (NRI) is one of prognostic factors in cardiovascular diseases, but little is known about its relation to the onset of cancer therapeutics-related cardiac dysfunction (CTRCD). Methods and Results: Consecutive 202 cancer patients planed for anthracycline treatment were enrolled and followed up for 12 months in our hospital from February 2017 to June 2019. The patients were divided into 2 groups based on NRI value at 100 before chemotherapy (high NRI group, n=141, 110.5 [104.7-115.6]; low NRI group, n=61, 93.7 [89.6-97.6]). Baseline left ventricular end systolic volume index and left ventricular ejection fraction (LVEF) before chemotherapy were similar between two groups. After chemotherapy, the occurrence of CTRCD was higher in low NRI group than in high NRI group (14.8% vs. 3.5%, P=0.012). Furthermore, there was a correlation between the severity of NRI categories and the development of CTRCD. When we set the cut-off value of baseline NRI from ROC analysis at 100.8, sensitivity, specificity, and area under the curve to predict the occurrence of CTRCD were 71.4%, 70.7%, and 0.698, respectively. Multivariable logistic regression analysis revealed that baseline NRI value was an independent predictor of the development of CTRCD (odds ratio 0.935, 95% CI [0.881-0.992], P=0.026). The value of net reclassification index and integrated discrimination improvement for detecting CTRCD reached statistical significance when baseline NRI value was added to the regression model including known risk factors such as age, female gender, the presence of hypertension, chronic kidney disease, cumulative anthracycline dose, the usage of HER2 inhibitor, and radiation therapy; 0.872 (95% CI [0.421-1.323], P Conclusion: Baseline NRI is a novel parameter to predict anthracycline-induced CTRCD.

Background: Patients with coronary artery disease who underwent percutaneous coronary intervention (PCI) are at high risk of bleeding due to antithrombotic therapy. However, the impact of bleeding event for new cancer diagnosis in patients after PCI remains unclear. Methods and Results: Consecutive 1623 patients with coronary artery disease who underwent PCI (mean age, 69.3 years; male gender, 78.5%) were enrolled. We examined a relationship between bleeding events and new cancer diagnosis. During a mean follow-up period of 48 months, 139 (8.6%) experienced bleeding events of Bleeding Academic Research Consortium (BARC) type-2/3/5, including 48 (3.0%) with BARC type-2 bleeding. Patients with bleeding event of BARC type-2/3/5 were older (72.4 vs. 68.9 years, P = 0.001), and higher prevalence of being at Academic Research Consortium criteria for high bleeding risk (72.3% vs. 46.4%, P < 0.001) than those without bleeding event. Among 1623 patients, 133 (8.2%) were diagnosed as having new cancer. The cumulative incidence of new cancer diagnosis was higher in patients with bleeding event of BARC type-2/3/5 than in those without bleeding event (P = 0.002, left figure). In addition, the cumulative incidence of new cancer diagnosis was higher in patients with bleeding event of BARC type-2 than in those without bleeding (P = 0.016, right figure). In the multivariate Cox proportional hazard analysis after adjusting for confounding factors, bleeding events of BARC type-2/3/5 and type-2 were independent predictors of new cancer diagnosis (hazard ratio 2.00, P = 0.007 and hazard ratio 2.25, P = 0.039, respectively). Conclusion: In patients with coronary artery disease after PCI, both major and minor bleeding events were associated with new cancer diagnosis. Even a minor bleeding event should be taken care as the first manifestation of underlying cancer after PCI.

Background: D-dimer is one of common measurable coagulation markers, that is associated with the risk of thrombotic events in vascular diseases. However, the impact of D-dimer on long-term mortality in coronary artery disease (CAD) patients remains unclear. Here we investigated the association between D-dimer and long-term mortality in CAD patients. Methods and Results: Consecutive 1440 patients with CAD who underwent percutaneous coronary intervention and survived to discharge were enrolled. We divided these patients into three groups based on plasma D-dimer levels at admission: first (D-dimer < 0.7 μg/ml, n = 455), second (0.7 ≤ D-dimer < 1.2, n = 453), and third (1.2 ≤ D-dimer, n = 532) tertiles. We compared clinical characteristics among three groups, and prospectively followed all-cause, cardiac, non-cardiac and cancer mortalities. Clinical characteristics for three groups were as follows; mean age (first tertile, second tertile, third tertile; 61.3 ± 11.3, 69.0 ± 10.8, 72.4 ± 10.8 years, P < 0.001), prevalence of chronic kidney disease (31.6%, 36.0%, 61.3%, P < 0.001), anemia (25.1%, 39.7%, 64.5%, P < 0.001), atrial fibrillation (10.8%, 14.1%, 19.7%, P < 0.001), peripheral artery disease (4.8%, 12.4%, 18.8%, P < 0.001) and heart failure (27.0%, 33.1%, 51.9%, P < 0.001). In the Kaplan-Meier analysis (mean follow-up periods 1572 days), all-cause, cardiac, non-cardiac and cancer mortalities were significantly higher in third tertile than others (P < 0.01, P < 0.01, P < 0.01 and P < 0.01, respectively). In the multivariable Cox proportional hazard analyses after adjusting for confounding factors, the high D-dimer level was an independent predictor of all-cause, cardiac, non-cardiac and cancer mortalities (HR 3.62, P < 0.01; HR 3.50, P < 0.01; HR 3.69, P < 0.01; and HR 3.17, P = 0.02). Conclusion: D-dimer is associated with long-term cause-specific mortality in CAD patients.

DNA damage is likely a key contributor to atherosclerosis. However, causative links between DNA damage and atherosclerosis are yet to be established. We investigated the role of DNA damage accumulation in atherosclerosis using the DNA repair protein Ku80-deficient apolipoprotein E knockout mice ( Ku80 +/- ApoE -/- ). Ku80 +/- ApoE -/- mice and ApoE -/- mice were fed on high-fat diet for 4 weeks. Oil red O staining showed that plaque area was significantly increased in Ku80 +/- ApoE -/- aortas. 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, MCP-1 and IFN-β in the aorta were significantly elevated in Ku80 +/- ApoE -/- mice than those of ApoE -/- control mice. To further investigate links between DSB accumulation and enhanced proinflammatory responses, vascular smooth muscle cells were isolated from Ku80 WT (WT) and Ku80 +/- mice. mRNA levels of IL-6, MCP-1 and IFN-β were significantly elevated in Ku80 +/- cells compared to those of WT cells. Immunofluorescent analysis revealed DSB accumulation and persistent activation of the DNA repair kinase ATM in Ku80 +/- cells. In addition, senescent markers such as p16 INK4A and senescence-associated β-gal activity were also upregulated in Ku80 +/- cells. Interestingly, the level of cytosolic DNA was elevated in Ku80 +/- cells. Furthermore, phosphorylation of TANK-binding kinase 1 was significantly increased in Ku80 +/- cells, indicating the activation of the cGAS-STING DNA sensing pathway. Thus, we performed cGAS or STING silencing in Ku80 +/- cells using siRNA to test whether cGAS-STING pathway was associated with enhanced proinflammatory responses. cGAS or STING silencing attenuated mRNA level of IL-6 and protein level of IκBα, the NFκB inhibitory protein. Taken together, these results suggested that the accumulation of DSBs promoted atherosclerosis partly through enhanced inflammatory responses via the cGAS-STING activation. Therefore, cGAS-STING may be a promising target for therapeutic intervention of atherosclerosis.

Introduction: The Japanese version of high bleeding risk (J-HBR) criteria have been established by modifying the Academic Research Consortium criteria for high bleeding risk (ARC-HBR), since East-Asian people have several distinct risk factors that were not included in ARC-HBR. We aimed to validate the J-HBR criteria for bleeding outcomes and compare with contemporary risk scores. Methods: Consecutive 1643 patients with coronary artery disease who underwent percutaneous coronary intervention were enrolled. We followed-up bleeding events of Bleeding Academic Research Consortium (BARC) 3 or 5. Results: Among 1643 patients, 1143 (69.6%) who met J-HBR criteria had a higher accumulated bleeding rate than those who did not (P < 0.001, left figure). BARC 3 or 5 bleeding event rates at 1 year were 4.8% in patients who met J-HBR criteria and 0.6% in those who did not (P < 0.01). The J-HBR criteria had higher sensitivity than ARC-HBR, PRECISE-DAPT and PARIS bleeding risk score (94.8%, 81.0%, 75.9% and 87.9%, respectively) and lower specificity than those (31.4%, 52.6%, 54.1% and 51.0%, respectively). J-HBR score was calculated by adding 1 point for major criterion and 0.5 point for minor criterion in J-HBR criteria. The bleeding event rate increased with advancing J-HBR score (right figure). The c-statistics of J-HBR score for predicting BARC 3 or 5 bleeding at 1 year was 0.74 (95% CI, 0.67 - 0.80) that was comparable to ARC-HBR score, PRECISE-DAPT score and PARIS bleeding risk score (0.73, 0.73 and 0.72, respectively). In the multivariate analysis, chronic kidney disease, anemia and heart failure were associated with BARC 3 or 5 bleeding (HR 6.39, P < 0.01; HR 3.38, P < 0.01; and HR 2.95, P < 0.01; respectively) among factors included in J-HBR criteria. Conclusions: The J-HBR criteria successfully identified patients at high bleeding risk, with high sensitivity and low specificity. The bleeding risk was closely related to J-HBR score and its individual component.

Purpose The purpose of this study was to investigate the safety and efficacy of high-power short-duration (HP-SD) ablation compared to conventional ablation in patients with atrial fibrillation (AF). Methods We enrolled consecutive 158 drug-refractory symptomatic AF patients (119 males, mean age 63 ± 10 years) who had undergone first radiofrequency pulmonary vein isolation (PVI). PVI was performed using the conventional setting (20–35 W) in 73 patients (Conventional group) and using the HP-SD setting (45–50 W) in 85 patients (HP-SD group). The rate of first pass isolation, remaining gaps after circumferential ablation, dormant conduction, and the radiofrequency application time in each pulmonary vein (PV) were compared between the groups. Results The first pass isolation ratio was significantly higher in the HP-SD group than in the Conventional group (81% vs. 65%, P = 0.027) in the right PV, but did not differ in the left PV. The remaining gaps were fewer in the right superior PV (4% vs. 21%, P = 0.001) and left inferior PV (1% vs. 8%, P = 0.032) areas, and the radiofrequency application time in each PV was shorter (right PV, 12.0 ± 8.9 min vs. 34.0 ± 31.7 min, P P Conclusion The use of the HP-SD setting might contribute to improve the first pass isolation rate and to shorten the radiofrequency application time in each PV.

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.

Background Homo sapiens have experienced admixture many times in the last few thousand years. To examine how admixture affects local adaptation, we investigated genomes of modern Polynesians, who are shaped through admixture between Austronesian-speaking people from Southeast Asia (Asian-related ancestors) and indigenous people in Near Oceania (Papuan-related ancestors). Methods In this study local ancestry was estimated across the genome in Polynesians (23 Tongan subjects) to find the candidate regions of admixture-enabled selection contributed by Papuan-related ancestors. Results The mean proportion of Papuan-related ancestry across the Polynesian genome was estimated as 24.6% (SD = 8.63%), and two genomic regions, the extended major histocompatibility complex (xMHC) region on chromosome 6 and the ATP-binding cassette transporter sub-family C member 11 (ABCC11) gene on chromosome 16, showed proportions of Papuan-related ancestry more than 5 SD greater than the mean (> 67.8%). The coalescent simulation under the assumption of selective neutrality suggested that such signals of Papuan-related ancestry enrichment were caused by positive selection after admixture (false discovery rate = 0.045). The ABCC11 harbors a nonsynonymous SNP, rs17822931, which affects apocrine secretory cell function. The approximate Bayesian computation indicated that, in Polynesian ancestors, a strong positive selection (s = 0.0217) acted on the ancestral allele of rs17822931 derived from Papuan-related ancestors. Conclusions Our results suggest that admixture with Papuan-related ancestors contributed to the rapid local adaptation of Polynesian ancestors. Considering frequent admixture events in human evolution history, the acceleration of local adaptation through admixture should be a common event in humans.

Extension of the focal depth of a sub-nanometer-sized electron probe in a scanning transmission electron microscope was demonstrated using an electron Bessel beam. We observed atomically-resolved annular dark-field scanning transmission electron microscope images of SrTiO3 in the [001] direction with defocus using an electron quasi-Bessel beam generated by a ring-shaped aperture in an aberration-corrected probe-forming system. The experimental results show that the defocus range over which images with a 0.2 nm spatial resolution can be acquired using the electron quasi-Bessel beam is three times longer than the corresponding defocus range for a conventional beam.

Ultrafast phenomena in gold nanotriangles (AuNTs) were investigated using a transient electron energy-loss spectroscopy (TEELS) technique under irradiation from a 150-fs pulse laser with a wavelength of 780 nm. This investigation was conducted using a time-resolved transmission electron microscopy method that was developed to measure the dynamics of nanomaterials. Enhancement of the intensity and energy-width broadening of the energy loss were observed at the EEL peaks associated with surface and bulk plasmons on the AuNTs. The TEELS measurement revealed two decay processes of 7.8 ps and longer than 100 ps that compensate for relaxation times of excited surface plasmons using transient absorption spectroscopy. The results show that the bulk and surface plasmons have the same time evolution, i.e., that the excited electrons on the surface and in the bulk have the same relaxation processes in both electron–phonon and phonon–phonon interactions. The time evolution of electronic and lattice temperatures was also estimated based on the measured relaxation time using a two-temperature model, which revealed the volume expansion of the AuNTs and clarified the energy shifts of plasmons. Details of excited electrons in nanoparticles investigated via plasmon energy loss are expected to facilitate improvement in the performance for energy harvesting of photons in nanostructure-controlled materials.

Background The Patterns of non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) thrombotic risk score has been proposed to estimate the risk of stent thrombotic events after percutaneous coronary intervention (PCI). However, the prognostic value of the PARIS thrombotic risk score for long term all-cause and cardiac mortalities, as well as hospitalization due to heart failure, has not yet been evaluated. Therefore, the aim of the present study was to evaluate the prognostic value of the PARIS thrombotic risk score for all-cause and cardiac mortalities and hospitalization due to heart failure following PCI. Methods and results Consecutive 1,061 patients who underwent PCI were divided into three groups based on PARIS thrombotic risk score; low- (n = 320), intermediate- (n = 469) and high-risk (n = 272) groups. We followed up on all three groups for all-cause mortality, cardiac mortality and hospitalization due to heart failure. Kaplan-Meier analysis showed that all outcomes were highest in the high-risk group (P < 0.001, P = 0.022 and P < 0.001, respectively). Multivariate Cox proportional hazard analysis, adjusted for confounding factors, showed that the risk of all-cause mortality and hospitalization due to heart failure of the high-risk group were higher than those of the low-risk group (hazard ratios 1.76 and 2.14, P = 0.005 and P = 0.017, respectively). Conclusion The PARIS thrombotic risk score is a significant prognostic indicator for all-cause mortality and hospitalization due to heart failure in patients after PCI.

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.

DNA suffers various types of damage even in a normal condition, although they are rapidly repaired by mechanisms called DNA repair. Most progeroid syndromes are caused by genetic defects in specific molecules involved in the DNA repair. DNA damage activates a broad range of signaling pathway that leads to repair, cell cycle arrest, apoptosis and so on, which is called DNA damage response. Recent studies revealed that persistent DNA damage response triggers induction of cell senescence and senescence-associated secretory phenotype (SASP). Here, we review recent advances in the understanding of the molecular mechanisms by which SASP components are regulated, and discuss the possible roles of DNA damage and the DNA damage response, and SASP in the pathogenesis of cardiovascular disease.

Group housing of socially-deprived individuals facilitates welfare and socialisation of primates. Here, we studied behavioural and hormonal changes in the course of group formation among nine male chimpanzees, Pan troglodytes. Aggression, reassurance, and grooming were observed in various dyads during group formation. The pattern of fluctuations in salivary cortisol level changed through the process of group formation, with particularly high cortisol levels immediately after group interactions relative to other sampling timings during group formation. Salivary testosterone levels were unaffected by the process of group formation or sampling time. These results suggested that a combination of behavioural observation and hormonal analyses is a powerful approach to assess the impact of group formation.

To validate Indonesian versions of two social/cultural psychological scales: the Self-Construal Scale (SCS) that measures independent and interdependent cultural values, and the Behavioral Inhibition (Avoidance) System and Behavioral Approach System (BIS/BAS) that measures motivation focus. We also explored the cultural background for the rising prevalence of depression in Indonesia.Case (hospital)-control (population) study.Hasanuddin University Hospital (cases) and Makassar city region (controls), Indonesia.Participants (N = 369) were 165 patients with depression recruited from a university hospital, and 204 healthy controls without a history of mental disorders recruited from locations within a 30-minute walk from the hospital.Depression was diagnosed by psychiatrists with reference to Indonesian mental disorder guidelines (Exploratory and confirmatory factor analyses showed that our revised 12-item SCS and the 13-item, three-factor BIS/BAS had a good model fit for the Indonesian population. MANCOVA showed that the SCS Independent subscale and the BAS subscales were significantly associated with depression after adjustment for age, sex, religion, education, and occupation.These findings may guide provision of appropriate treatment for patients based on their social and cultural environment. In addition, this study contributes to understanding underlying reasons for the increasing prevalence of depression in Indonesia, where society is changing from traditional collectivism to global individualism.

Objectives Semenogelin 1 and 2 (SEMG1 and SEMG2) are known as semen coagulating proteins in primates with a repetitive structure of 60-amino acids. The number of repeats varies among species and is hypothesized to be related to the level of primate sperm competition. Gibbons until recently were thought to be monogamous primates, but it is now known that gibbon social structure is flexible. Thus, hypotheses of the relationship between the SEMGs evolution and mating systems were tested. Materials and methods The sequences of the exon 2 of the SEMG1 and SEMG2 were obtained from 50 captive gibbons comprising six species belonging to three genera (Hylobates, Symphalangus, and Nomascus). Then we quantified the levels of polymorphism and estimated rates of protein evolution by calculating d N /d S ratio. Results Several mutations that create a premature stop codon in the SEMG1 and a reduction in the repeats of the SEMG2 in the genus Hylobates were observed and may alter the coding properties for these proteins. We also found different level of nucleotide diversity in each gene and between genera. Strikingly, in Nomascus leucogenys we discovered a high d N /d S ratio in the SEMG1 and SEMG2. The Nomascus SEMG2 also showed significantly lower nucleotide diversity than the other two genera. Discussion These results are consistent with the presence of a strong positive selection in the Nomascus lineage even if the exact selective forces acting on these genes are not yet conclusively known. We were not able to demonstrate, among gibbons, unambiguous relationships between the SEMGs evolution and mating systems.

We investigate the intensity interference between pairs of electrons using a spin-polarized electron beam having a high polarization and a narrow energy width. We observe spin-dependent antibunching on the basis of coincident counts of electron pairs performed with a spin-polarized transmission electron microscope, which could control the spin-polarization without any changes in the electron optics. The experimental results show that the time correlation was only affected by the spin polarization, demonstrating that the antibunching is associated with fermionic statistics. The coherent spin-polarized electron beam facilitates the extraction of intrinsic quantum interference.

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.