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Summary: Background: Repeated topical application of indomethacin is common in Japanese racehorses, despite the lack of pharmacokinetic data. Objectives: To determine the concentrations of indomethacin and its metabolite, desmethylindomethacin, in plasma and urine of Thoroughbreds topically treated repeatedly with indomethacin. Study design: In vivo experimental. Methods: Seven female Thoroughbreds were topically treated with 50 g of 1% indomethacin cream per horse to the back and hips (500 mg of indomethacin/head/2400 cm2, 0.21 g/cm2) for 3 consecutive days. Samples were pretreated by protein precipitation for plasma and liquid‐liquid extraction with ethyl acetate after hydrolysis with hydrochloric acid for urine. The concentrations of indomethacin and desmethylindomethacin in plasma and urine were measured by liquid chromatography‐mass spectrometry. Results: Indomethacin was quantifiable in plasma up to 48–72 h and in urine up to 96 h after the final application. Desmethylindomethacin was quantifiable in plasma up to 48 h and in urine up to 72–96 h after the final application. Main limitations: The relationship between the local and systemic indomethacin concentrations after the topical application was not clarified. Conclusions: Pharmacokinetic data were acquired for repeated topical administration of 1% indomethacin cream to Thoroughbreds. Hydrolysing urine samples with hydrochloric acid was effective for the analysis of indomethacin and its metabolite, and indomethacin may be an excellent marker analyte for doping tests. The estimated withdrawal time based on the limit of detection was 342 h. [ABSTRACT FROM AUTHOR]

We developed 12 polymorphic microsatellite markers from a salt-marsh sedge Carex rugulosa. The number of alleles per locus ranged from two to four, with an average of 2.75. The observed and expected heterozygosities ranged from 0.067 to 0.600 and from 0.128 to 0.620, respectively. These simple sequence repeat markers will allow the identification of genets and evaluation of the genetic diversity of C. rugulosa. [ABSTRACT FROM AUTHOR]

Competing Interests: There are no conflicts of declaration.

Objective: Osilodrostat, used to treat Cushing's disease, exhibits an anabolic effect, leading to its classification as a prohibited substance in horseracing and equestrian sports. This study reports the characterization of osilodrostat metabolites in horse urine and elucidates its metabolic pathways for the first time for doping control purposes., Methods: Osilodrostat was administered nasoesophageally to four thoroughbreds (one gelding and three mares) at a dose of 50 mg each. Potential metabolites were extensively screened via our developed generic approach employing differential analysis to identify metabolites. Specifically, high-resolution mass spectral data were compared between pre- and post-administration samples on the basis of criteria of fold-changes of peak areas and their P values. Potential metabolite candidates were further identified through mass spectral interpretations using product ion scan data., Results: A total of 37 metabolites were identified after comprehensive analysis. Osilodrostat was predominantly metabolized into a mono-hydroxylated form M1c (~40%) alongside osilodrostat glucuronide M2 (~17%). Given their longest detection time (2 weeks after administration) and the identification of several conjugates of osilodrostat and M1c, including a novel conjugate of riburonic acid, we recommend monitoring both osilodrostat and M1c after hydrolysis during the screening stage. However, only osilodrostat can be used for confirmation because of the availability of a reference material., Conclusion: It is advisable to screen for both osilodrostat and its mono-hydroxylated metabolite M1c to effectively monitor horse urine for the potential misuse or abuse of osilodrostat. For suspicious samples, confirmation of osilodrostat using its reference material is required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: The use of osilodrostat, developed as a medication for Cushing's disease but categorized as an anabolic agent, is banned in horses by both the International Federation of Horseracing Authorities and the Fédération Equestre Internationale. For doping control purposes, elimination profiles of hydrolyzed osilodrostat in horse urine were established and the detectability of free forms of osilodrostat and its major metabolite, mono-hydroxylated osilodrostat (M1c), was investigated. Materials & methods: Post-administration urine samples obtained from a gelding and three mares were analyzed to establish the elimination profiles of osilodrostat using a validated method involving efficient enzymatic hydrolysis followed by LC/ESI-HRMS analysis. Results: Applying the validated quantification method with an LLOQ of 0.05 ng/ml, hydrolyzed osilodrostat could be quantified in post-administration urine samples from 48 to 72 h post-administration; by contrast, both hydrolyzed osilodrostat and M1c were detected up to 2 weeks. In addition, confirmatory analysis identified the presence of hydrolyzed osilodrostat for up to 72 h post-administration. Conclusion: For doping control purposes, we recommend monitoring both hydrolyzed M1c and osilodrostat because of the greater detectability of M1c and the availability of a reference material of osilodrostat, which is essential for confirmatory analysis.

Paravalvular leakage (PVL) is a complication of transcatheter aortic valve implantation (TAVI) for aortic stenosis, leading to an adverse prognosis. We investigated whether aortic valve calcium volume (Ca-Vol) measured by preoperative cardiac computed tomography had a predictive value for PVL after TAVI using a third-generation self-expandable valve.We retrospectively analyzed 59 consecutive patients who underwent TAVI using a third-generation self-expandable valve. We measured Ca-Vol in the aortic valve and each cusp (non-coronary cusp [NCC], right-coronary cusp [RCC], and left-coronary cusp [LCC]). We divided the patients into 2 groups: a PVL group (32.2%) and a non-PVL group (67.8%). Total Ca-Vol was significantly higher in the PVL group than in the non-PVL group (P < 0.001). Ca-Vol in each cusp was also significantly higher in the PVL group ([NCC] P < 0.001, [RCC] P = 0.001, [LCC] P < 0.001). Univariate logistic regression analysis for PVL indicated that the total and per-cusp Ca-Vols were predictors for PVL (total, odds ratio [OR] 4.0, P < 0.001; NCC, OR 12.5, P = 0.002; RCC, OR 16.0, P = 0.008; LCC, OR 44.5, P < 0.001).Receiver operating characteristic curve analysis of Ca-Vol for predicting PVL revealed the optimal cut-off values of Ca-Vol were 2.4 cm 3 for the total, 0.74 cm 3 for NCC, 0.73 cm 3 for RCC, and 0.56 cm 3 for LCC (area under the curve, 0.85, 0.79, 0.76, and 0.83, respectively).Preoperative total, NCC, RCC, and LCC calcium volumes were significant predictors for PVL after TAVI using third-generation self-expandable valves.

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., Competing Interests: The authors have declared that no competing interests exist.

Two sediment core samples from the brackish Lake Nakaumi in Japan were analyzed to determine the historical profiles of organochlorine pesticides (OCPs). It was observed that from the 1940s to 2005, the vertical distribution of OCPs in sediment cores reflected the temporal trend of pesticide usage in Japan. Dichlorodiphenyltrichloroethane (DDT) and its metabolites were predominant, with concentrations of 0.008-8.27 ng g -1 dry weight, and their contribution to ΣOCPs was over 58%. The results also confirmed that the DDTs in the sediment cores originated from past input. Further, even though hexachlorocyclohexanes were the most used OCP in Japan, their residual concentrations were lower than those of DDTs and chlordane related compounds (CHLs). The concentrations of CHLs were 0.163-1.539 ng g -1 dry weight, whereas hexachlorobenzene (HCB), drins, heptachlor, and mirex showed very low concentrations. Interestingly, although HCB was never registered as a pesticide in Japan, it was detected in both core samples. This HCB contamination might be attributed to pentachlorophenol. Additionally, the hierarchical cluster analysis results corresponding to both sediment cores could be classified under four groups based on a similarity of over 50%. The results also showed that the OCP burden in Lake Nakaumi for the past 60 years was 130 kg and 1153 kg at Honjo and at the center of Lake Nakaumi, respectively. Overall, the results of this study indicate that the distribution of OCPs in Lake Nakaumi reflects the trend of pesticide usage in Japan., (Copyright © 2021. Published by Elsevier Ltd.)

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 (P < 0.001, P < 0.001 and P < 0.001 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 P < 0.001, respectively). The PARIS bleeding risk score is a significant indicator of prognosis for all-cause mortality in patients after PCI.

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 (P < 0.05 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.

Objective: Heart failure (HF) is a common and highly morbid cardiovascular disorder. Oxidative stress worsens HF, and uric acid (UA) is a useful oxidative stress marker. The novel anti-hyperuricemic drug febuxostat is a potent non-purine selective xanthine oxidase inhibitor. The present study examined the UA-lowering and prognostic effects of febuxostat in patients with HF compared with conventional allopurinol., Methods: This multicenter, randomized trial included 263 patients with chronic HF who were randomly assigned to two groups and received allopurinol or febuxostat (UA >7.0 mg/dL). All patients were followed up for 3 years after enrollment., Results: There were no significant differences in baseline clinical characteristics between the two groups. The UA level was significantly decreased after 3 years of drug administration compared with the baseline in both groups. Urine levels of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine were lower in the febuxostat group than in the allopurinol group (11.0 ± 9.6 vs. 22.9 ± 15.9 ng/mL), and the rate of patients free from hospitalization due to worsening HF tended to be higher in the febuxostat group than in the allopurinol group (89.0% vs. 83.0%)., Conclusions: Febuxostat is potentially more effective than allopurinol for treating patients with chronic HF and hyperuricemia.This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/; ID: 000009817).

Heat stress adversely affects the reproductive function in cows. Although a relationship between heat stress and oxidative stress has been suggested, it has not been sufficiently verified in bovine endometrial epithelial cells. Here, we investigated whether oxidative stress is induced by heat stress in bovine endometrial epithelial cells under high temperature. Luciferase reporter assays showed that the reporter activity of heat shock element and antioxidant responsive element was increased in endometrial epithelial cells cultured under high temperature compared to that in cells cultured under basal (thermoneutral) temperature. Also, nuclear factor, erythroid 2 like 2 (NFE2L2), a master regulator of cellular environmental stress response, stabilized and the expression levels of antioxidant enzyme genes increased under high temperature. Immunostaining confirmed the nuclear localization of NFE2L2 in endometrial epithelial cells cultured under high temperature. Quantitative polymerase chain reaction analysis showed that the expression levels of representative inflammatory cytokine genes, such as prostaglandin-endoperoxide synthase 2 (PTGS2) and interleukin 8, were significantly decreased in endometrial epithelial cells cultured under high temperature compared to those in cells cultured under basal temperature. Thus, our results suggest that heat stress induces oxidative stress, whereas NFE2L2 plays a protective role in bovine endometrial epithelial cells cultured under heat stress conditions., (© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The zona pellucida (ZP) plays an important role in both the fertilization and embryonic development. For the successful handling of early stage blastomeres for differentiation analysis, the production of identical twins or quadruplets, nuclear transfer or gene introduction requires the removal of the ZP (ZPR). Although single use of either acidic Tyrode's solution or pronase are commonly used for ZPR, long-term exposure to these agents can result in the inhibition of development with the collapse of the three-dimensional blastomere structure. Here, we demonstrate the benefits of using a two-step combined ZPR method, which relies upon a customized well-of-well (cWOW) system with smaller well size, on developmental competence and the quality of the zona free (ZF) mouse embryos. We first isolated 2-cell embryos using acid Tyrode's solution and then cultured these embryos using either commercially available or cWOW, which had a smaller microwell size. The rate of blastocyst was significantly increased by use of cWOW when compared to other culture systems. Then we evaluated the use of a two-step ZPR protocol, relying on acid Tyrode's solution and proteinase K, and subsequent culture in the cWOW system. Although acid Tyrode's solution treatment alone reduced ZPR time, blastomere morphology became wrinkled, significant decrease in blastocyst rate associated with increased number of apoptotic cells and increased expression of apoptosis-related genes were observed. Using proteinase K alone increased ZPR time and significantly decreased the blastocyst rate, but did not induce an increase in apoptotic cell number or apoptosis-related gene expression. In contrast, two-step method significantly reduced ZPR time and improved blastocyst rate by increasing the total number of cells in these wells an reducing the number of apoptotic cells in these experiments. These results suggest that the two-step ZPR protocol is beneficial for reducing the toxic effects of zona removal on ZF embryo development and quality when combined with a suitable culture system., Competing Interests: Declaration of competing interest This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The present study was performed to compare the relationship of 18 F-fluorodeoxyglucose (FDG) uptake and late gadolinium enhancement (LGE) transmurality with the improvement of left ventricular function in patients with coronary chronic total occlusion (CTO) assessed by hybrid FDG positron emission tomography (PET)/magnetic resonance imaging (MRI)., Methods: Thirty-eight consecutive patients with CTO underwent FDG PET/MRI. Twenty-three patients then underwent percutaneous coronary intervention (PCI), and the final study population comprised 15 patients who underwent both initial and follow-up MRI. The degree of wall motion abnormality in each of the 17 myocardial segments was evaluated based on the extent of wall thickening on cine MRI using a 5-point scale., Results: Among all 646 myocardial segments at baseline, FDG uptake significantly decreased as the transmurality of LGE is advanced. Of the 15 patients who underwent PCI, 152 segments showed wall motion abnormalities at baseline. The functional recovery of the wall motion abnormality of the PET-viable/MRI-viable segments was highest, and that of the PET-nonviable/MRI-nonviable segments was lowest. There were no differences in functional recovery between the PET-viable/MRI-nonviable and PET-nonviable/MRI-viable segments., Conclusion: Simultaneous assessment of FDG and LGE using a hybrid PET/MRI system can help to predict functional recovery after PCI in patients with CTO., (© 2020. American Society of Nuclear Cardiology.)

An early and accurate pregnancy diagnosis method is required to improve the reproductive performance of cows. Here we developed an easy pregnancy detection method using vaginal mucosal membrane (VMM) with application of Reverse Transcription-Loop-mediated Isothermal Amplification (RT-LAMP) and machine learning. Cows underwent artificial insemination (AI) on day 0, followed by VMM-collection on day 17-18, and pregnancy diagnosis by ultrasonography on day 30. By RNA sequencing of VMM samples, three candidate genes for pregnancy markers (ISG15 and IFIT1: up-regulated, MUC16: down-regulated) were selected. Using these genes, we performed RT-LAMP and calculated the rise-up time (RUT), the first-time absorbance exceeded 0.05 in the reaction. We next determined the cutoff value and calculated accuracy, sensitivity, specificity, positive prediction value (PPV), and negative prediction value (NPV) for each marker evaluation. The IFIT1 scored the best performance at 92.5% sensitivity, but specificity was 77.5%, suggesting that it is difficult to eliminate false positives. We then developed a machine learning model trained with RUT of each marker combination to predict pregnancy. The model created with the RUT of IFIT1 and MUC16 combination showed high specificity (86.7%) and sensitivity (93.3%), which were higher compared to IFIT1 alone. In conclusion, using VMM with RT-LAMP and machine learning algorithm can be used for early pregnancy detection before the return of first estrus., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective It has been reported that anti-mitochondrial antibodies (AMAs) recognize mitochondrial antigens and are associated with some diseases involving multiple organs, such as primary biliary cholangitis, Sjögren syndrome, Hashimoto's thyroiditis, systemic sclerosis, interstitial pneumoniae, dilated cardiomyopathy, and tubulointerstitial nephritis. In the current study, we examined the prevalence of AMAs in patients with dilated cardiomyopathy (DCM) and their clinical characteristics. Methods We enrolled 270 patients with DCM. We measured serum AMAs and analyzed the associated factors. Out of the 270 patients, positive AMAs were detected in 3 patients (1.1%; mean age, 68 years old; 2 men). These three patients had a significantly higher prevalence of primary biliary cholangitis and myopathy and levels of alanine alkaline phosphatase than those who were negative for said antibodies. There were no significant differences in the levels of B-type natriuretic peptide, aspartate transaminase, and left ventricular ejection fraction between these groups of patients. During the follow-up period, two of the three patients died due to respiratory failure. The other patient survived but experienced type II respiratory failure. Conclusion The prevalence of AMAs in 270 DCM patients was only 1.1%, and these patients suffered from respiratory failure.

Background: The Glasgow-Blatchford Score (GBS) is one of the most widely used scoring systems for predicting clinical outcomes for gastrointestinal bleeding (GIB). However, the clinical significance of the GBS in predicting GIB in patients with heart failure (HF) remains unclear., Methods and Results: We conducted a prospective observational study in which we collected the clinical data of a total of 2236 patients (1130 men, median 70 years old) who were admitted to Fukushima Medical University Hospital for acute decompensated HF. During the post-discharge follow-up period of a median of 1235 days, seventy-eight (3.5%) patients experienced GIB. The GBS was calculated based on blood urea nitrogen, hemoglobin, systolic blood pressure, heart rate, and history of hepatic disease. The survival classification and regression tree analysis revealed that the accurate cut-off point of the GBS in predicting post-discharge GIB was six points. The patients were divided into two groups: the high GBS group (GBS > 6, n = 702, 31.4%) and the low GBS group (GBS ≤ 6, n = 1534, 68.6%). The Kaplan-Meier analysis showed that GIB rates were higher in the high GBS group than in the low GBS group. Multivariate Cox proportional hazards analysis adjusted for age, malignant tumor, and albumin indicated that a high GBS was an independent predictor of GIB (hazards ratio 2.258, 95% confidence interval 1.326-3.845, p = 0.003)., Conclusions: A high GBS is an independent predictor and useful risk stratification score of post-discharge GIB in patients with HF.

Purpose: Atrial fibrillation (AF) often coexists with atrial septal defects (ASD). Each of the transcatheter closure for ASD and radiofrequency catheter ablation (RFCA) for AF have been established as the first-line therapy. However, there are limited data about therapeutic effect RFCA plus transcatheter ASD closure on AF recurrence in AF patients with ASD. The aim of the current study was to investigate the clinical impact of ASD closure following RFCA on AF recurrence., Methods: Forty-two ASD patients (17 males and 54 ± 20 years old) were enrolled and classified into three groups: ASD occlusion-sinus rhythm (ASO-SR) (n = 26), no AF history prior to ASD closure; ASO-AF-RFCA (n = 11), RFCA was performed due to AF history before ASD closure; and ASO-AF-anti-arrhythmic drug (ASO-AF-AAD) (n = 5), AF was treated with AAD before and after ASD closure. AF occurrence among the 3 groups was evaluated., Results: Kaplan-Meier analysis showed that ASO-SR and ASO-AF-RFCA groups showed a lower AF occurrence ratio than ASO-AF-AAD group during the 14- ± 9-month follow-up periods (P = 0.013). AF occurrence in ASO-SR and ASO-AF-RFCA groups was comparable (P = 0.480). Bi-atrial reverse remodeling, such as decrease in left atrial volume index (P = 0.049) and right atrial area (P = 0.046), and significant decrease in high-sensitivity C-reactive protein levels (P = 0.049) were identified in ASO-AF-RFCA group, but not in ASO-AF-AAD group., Conclusion: A combination of two percutaneous therapies was proven to be effective and induced bi-atrial reverse remodeling in association with inflammatory reaction.

Aims: Recently, B-type natriuretic peptide (BNP) has been attracting attention as a predictor of stroke in patients with atrial fibrillation or those with prior stroke experience. However, the association between BNP and stroke has not been examined in patients with chronic heart failure (CHF). In the current study, we assessed whether BNP is associated with future occurrence of stroke in patients with CHF., Methods and Results: We prospectively studied 1803 consecutive patients who were admitted for decompensated HF and assessed the predictive value of circulating BNP levels for occurrence of post-discharge stroke. A total of 69 (3.8%) patients experienced a stroke (the stroke group) during the post-discharge follow-up period of a median of 1150 days. The stroke group showed a higher CHADS 2 score. With respect to past medical history, the stroke group had a higher prevalence of arterial hypertension, atrial fibrillation, prior stroke, and chronic kidney disease. Echocardiographic parameters showed no significant differences between the two groups. In contrast, BNP levels were significantly higher in the stroke group than in the non-stroke group (452.1 vs. 222.7 pg/mL, P < 0.001). Multivariate Cox proportional hazard analysis indicated that BNP levels were independently associated with post-discharge stroke (hazard ratio 2.636, 95% confidence interval 1.595-4.357, P < 0.001). The survival classification and regression tree analysis revealed that the accurate cut-off point of BNP in predicting post-discharge stroke was 187.7 pg/mL. We added high BNP level (BNP ≥ 180 pg/mL) as one point to CHADS 2 score. The BNP-added CHADS 2 score was compared with CHADS 2 score alone by using c-statistics. The areas under the curve of CHADS 2 score, BNP, and BNP-added CHADS 2 score were 0.698, 0.616, and 0.723, respectively. The predictive value of BNP-added CHADS 2 score was higher compared with those of CHADS 2 score (P = 0.026)., Conclusions: The assessment of BNP may predict the occurrence of stroke in CHF patients used alone or in combination with established CHADS 2 score., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Sleep-disordered breathing (SDB) and blood pressure variability (BPV) are strongly associated with cardiovascular diseases. Recently, pulse transit time (PTT) has enabled the monitoring of beat-to-beat BP; however, little is known about its clinical utility. The present study aimed to clarify the impact of SDB on very short-term BPV determined by PTT-based BP monitoring (PTT-BP)., Methods: We analyzed 242 patients with suspected SDB. PTT-BP was continuously recorded overnight together with a portable sleep monitor. PTT index was defined as the average number of transient rises in PTT-BP (≥12 mmHg) within 30 s/h. We compared PTT-BP values with each SDB parameter, and examined the association between BPV and subclinical organ damage., Results: Standard deviation (SD) of systolic, mean or diastolic PTT-BP, which indicates very short-term BPV, was significantly correlated with apnea--hypopnea index (AHI) and oxygen desaturation index (ODI). PTT index was positively associated with AHI, ODI, and minimal SpO2. Regression analyses showed that AHI and ODI were significant variables to determine systolic, mean, or diastolic PTT-BP SD and PTT index. Logistic regression analyses demonstrated that diastolic PTT-BP SD significantly influenced the presence of chronic kidney disease and left ventricular hypertrophy., Conclusion: SDB severity was closely associated with very short-term BP variability, and diastolic PTT-BP SD might be an important factor linked to subclinical organ damage. PTT-BP measurement may be useful to evaluate very short-term BPV during the night.

Background It has been reported that liver stiffness assessed by transient elastography are correlated with right atrial pressure, which is associated with worse outcome in patients with heart failure (HF). We aimed to clarify clinical implications of hepatic hemodynamic evaluation (liver congestion and hypoperfusion) by abdominal ultrasonography in patients with HF. Methods and Results We performed abdominal ultrasonography, right-heart catheterization, and echocardiography, then followed up for cardiac events such as cardiac death or worsening HF in patients with HF. Regarding liver congestion, liver stiffness assessed by shear wave elastography (SWE) of the liver was significantly correlated with right atrial pressure determined by right-heart catheterization ( R =0.343; P <0.01), right atrial end-systolic area, and inferior vena cava diameter determined by echocardiography. Regarding liver hypoperfusion, peak systolic velocity (PSV) of the celiac artery was correlated with cardiac index determined by right-heart catheterization ( R =0.291; P <0.001) and tricuspid annular plane systolic excursion determined by echocardiography. According to the Kaplan-Meier analysis, HF patients with high SWE and low PSV had the highest cardiac event rate (log-rank P =0.033). In the Cox proportional hazard analysis, high SWE and low PSV were associated with high cardiac event rate (high SWE: hazard ratio [HR], 2.039; 95% CI, 1.131-4.290; low PSV: HR, 2.211; 95% CI, 1.199-4.449), and the combination of high SWE and low PSV was a predictor of cardiac events (HR, 4.811; 95% CI, 1.562-14.818). Conclusions Intrahepatic congestion and hypoperfusion determined by abdominal ultrasonography (liver SWE and celiac PSV) are associated with adverse prognosis in patients with HF.

Background: The predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score predicts the risk of bleeding in patients treated with dual antiplatelet therapy after percutaneous coronary intervention. Although the PRECISE-DAPT score is expected to be useful beyond its original field, long-term prognostic value of this score in patients with acute myocardial infarction (AMI) remains unclear. In the current study, we aimed to investigate the performance of the PRECISE-DAPT score in predicting the long-term prognosis in patients with AMI., Methods and Results: Consecutive 552 patients with AMI, who had been discharged from our institution, were enrolled. We divided the patients into three groups, based on their PRECISE-DAPT scores: the low (PRECISE-DAPT < 17), intermediate (17-24) and high (≥25) score groups. Kaplan-Meier analysis (mean follow-up 1424 days) revealed that all-cause mortality increased most steeply in the high score group followed by the intermediate and low score groups (P < 0.001). After adjusting for possible confounding factors, mortality of the intermediate or high score groups were higher than those of low score group (HR 2.945, 95% CI 1.182-7.237, P = 0.020, and HR 5.567, 95% CI 2.644-11.721, P < 0.001, respectively)., Conclusions: In patients with AMI, a high PRECISE-DAPT score was associated with higher long-term all-cause mortality. PRECISE-DAPT score is useful for predicting all-cause mortality, as well as risk stratification of bleeding., (© 2020 The Authors. Published by Elsevier B.V.)

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 <0.001), and showed a higher use of loop diuretics (77.9% versus 67.8%; 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 mEq/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: It has been reported that recovery of left ventricular ejection fraction (LVEF) is associated with better prognosis in heart failure (HF) patients with reduced EF (rEF). However, change of LVEF has not yet been investigated in cases of HF with preserved EF (HFpEF)., Methods and Results: Consecutive 1082 HFpEF patients, who had been admitted to hospital due to decompensated HF (EF >50% at the first LVEF assessment at discharge), were enrolled, and LVEF was reassessed within 6 months in the outpatient setting (second LVEF assessment). Among the HFpEF patients, LVEF of 758 patients remained above 50% (pEF group), 138 patients had LVEF of 40%-49% (midrange EF, mrEF group) and 186 patients had LVEF of less than 40% (rEF group). In the multivariable logistic regression analysis, younger age and presence of higher levels of troponin I were predictors of rEF (worsened HFpEF). In the Kaplan-Meier analysis, the cardiac event rate of the groups progressively increased from pEF, mrEF to rEF (log-rank, p<0.001), whereas all-cause mortality did not significantly differ among the groups. In the multivariable Cox proportional hazard analysis, rEF (vs pEF) was not a predictor of all-cause mortality, but an independent predictor of increased cardiac event rates (HR 1.424, 95% CI 1.020 to 1.861, p=0.039)., Conclusion: An initial assessment of LVEF and LVEF changes are important for deciding treatment and predicting prognosis in HFpEF patients. In addition, several confounding factors are associated with LVEF changes in worsened HFpEF patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

It has been recently recognized that recovery of left ventricular ejection fraction (EF), termed "recovered EF", occurs in a proportion of heart failure patients with reduced EF (HFrEF), and is associated with better prognosis. However, the clinical characteristics of "recovered EF" have not been fully examined.Consecutive 567 patients hospitalized due to HFrEF (EF < 40% at 1st assessment at hospital discharge) were enrolled, and EF was re-assessed within half a year in an outpatient setting (2nd assessment). Among these HFrEF patients, 235 remained EF < 40% (reduced, rEF group), 82 changed to EF 40-49% (midrange, mrEF group), and 250 recovered to EF > 50% (preserved, pEF group "recovered EF" ) at the 2nd examination. Age was lower and body mass index and systolic blood pressure were higher in pEF than in rEF. The prevalence of atrial fibrillation (AF) and usage of an implantable cardiac defibrillator and cardiac resynchronization therapy were highest in pEF. Left ventricular end diastolic dimension (LVDd) was the smallest in the pEF group. Multivariable logistic regression analysis revealed that younger age, presence of AF, and lower levels of LVDd were predictors of "recovered EF". Kaplan-Meier analysis found that pEF presented the lowest cardiac event rate (P = 0.003) and all-cause mortality (P = 0.001). In multivariable Cox proportional hazard analyses, pEF (versus rEF) was an independent predictor of both cardiac event rate (HR = 0.668, 95%CI 0.450-0.994, P = 0.046) and all-cause mortality (HR = 0.655, 95%CI 0.459-0.934, P = 0.019).Hospitalized HFrEF patients with recovered EF are associated with younger age, higher presence of AF, and better prognosis.

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 (<10, n=98). During the median follow-up period of 1,581 days (range, 20-2,896 days), the high-score patients had a higher cardiac mortality than the low-score group (log rank, P=0.001). Conclusions: In patients with HF after PCI, residual Gensini score was associated with long-term cardiac mortality. Residual Gensini score may be a useful index for risk stratification of HF after PCI., Competing Interests: T. Yokokawa belongs to a department supported by Actelion Pharmaceuticals Japan. A.Y. and T.M. belong to a department supported by Fukuda Denshi. These companies are not associated with the contents of this study. The other authors declare no conflicts of interest., (Copyright © 2020, THE JAPANESE CIRCULATION SOCIETY.)

Objective: To clarify whether cardiac cachexia (CC) alters the prognostic impact of other general risk factors in patients with heart failure (HF)., Methods: This was an observational study. CC was defined as the combination of a body mass index of < 20 kg/m 2 and at least one of the following biochemical abnormalities: C-reactive protein > 5 mg/L; hemoglobin < 12 g/dL; and/or albumin < 3.2 g/dL. We divided 1608 hospitalized HF patients into a CC group ( n = 176, 10.9%) and a non-CC group ( n = 1432, 89.1%). The primary endpoints were cardiac event and all-cause death., Results: The presence of CC showed significant interactions with other risk factors including cancer, estimated glomerular filtration rate (eGFR), and sodium in predicting these endpoints. Multiple Cox proportional analysis revealed that use of â blockers [hazard ratio (HR) = 1.900, 95% confidence interval (CI): 1.045-3.455, P = 0.035) and eGFR (HR = 0.989, 95% CI: 0.980-0.998, P = 0.018) were independent predictors of cardiac event in the CC group, while age (HR = 1.020, 95% CI: 1.002-1.039, P = 0.029) and hemoglobin (HR = 0.844, 95% CI: 0.734-0.970, P = 0.017) were independent predictors of all-cause death. The survival classification and regression tree analysis showed the optimal cut-off points for cardiac event (eGFR: 59.9 mL/min per 1.73 m 2 ) and all-cause death (age, 83 years old; hemoglobin, 10.1 g/dL) in the CC group., Conclusions: In predicting prognosis, CC showed interactions with several risk factors. Renal function, age, and hemoglobin were pivotal markers in HF patients with CC., (Institute of Geriatric Cardiology.)

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 DPG < 7 mmHg; Group B, patients with either PVR > 3 WU or DPG ≥ 7 mmHg; and Group C, patients with PVR > 3 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.

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.