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Patients with chronic coronary syndrome (CCS), even when they have complete revascularization and normal left ventricular (LV) systolic function, experience subsequent cardiovascular disease (CVD), highlighting the importance of surrogate markers to prevent adverse consequences. Speckle-tracking echocardiography-derived left atrial (LA) reservoir strain has emerged as a sensitive marker for CVD in various clinical settings. The present study investigated the prevalence, determinants, and prognostic value of LA dysfunction in CCS. We included 278 consecutive patients with CCS with completed percutaneous coronary intervention and preserved LV ejection fraction who underwent follow-up echocardiography. Speckle-tracking analysis was performed to assess LA reservoir strain, and LA dysfunction was defined as LA reservoir strain ≤24%. The primary outcome comprised new-onset atrial fibrillation, heart failure hospitalization, acute coronary syndrome, stroke, or all-cause death. At baseline, 28 patients (10.1%) had LA dysfunction. Multivariable analysis identified age, hypertension, LV ejection fraction, and multivessel disease as independent determinants of LA reservoir strain (all p0.05). During a median follow-up of 4.8 years, the primary outcome occurred in 60 patients (21.6%). LA dysfunction carried a significant risk for primary outcome independent of traditional risk factors, LV parameters, and LA size (adjusted hazard ratio 3.10, p = 0.003); the risk increase remained significant even after excluding atrial fibrillation from the primary outcome (adjusted hazard ratio 2.27, p = 0.043). In conclusion, approximately 10% of patients with CCS with normal LV ejection fraction had LA dysfunction associated with adverse cardiovascular outcomes. Further studies are needed to explore whether therapeutic interventions affecting LA remodeling may help prevent CVD events.

The cost-effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors for chronic kidney disease (CKD) has not been evaluated in Japan, so we analyzed the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor, for CKD stages 3a and 3b.Methods and Results: We used the Markov model for CKD to assess the costs and benefits associated with and without dapagliflozin from a health system perspective. We estimated the incremental cost-effectiveness ratio (ICER), expressed as per quality-adjusted life-years (QALYs). An ICER5 million Japanese yen (JPY)/QALY was judged to be cost-effective. The effect of dapagliflozin on renal and cardiovascular events was based on published clinical trials. In patients with CKD stage 3a, the ICER of dapagliflozin over standard treatment was 4.03 million JPY/QALY gained. With a cost-effectiveness threshold of 5 million JPY/QALY gained, the cost-effectiveness probability of dapagliflozin over standard treatment was 52.6%. In patients with CKD stage 3b, the ICER of dapagliflozin over standard treatment was 0.12 million JPY/QALY gained. The cost-effectiveness probability of dapagliflozin over standard treatment was 75.2%.The results seemed to show acceptable cost-effectiveness when dapagliflozin was used for CKD stage 3b. On the other hand, cost-effectiveness of dapagliflozin for CKD stage 3a was ambiguous, and further validation is needed.

Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Left ventricular dilatation (LVD) and left ventricular hypertrophy (LVH) are risk factors for heart failure, and their detection improves heart failure screening. This study aimed to investigate the ability of deep learning to detect LVD and LVH from a 12-lead electrocardiogram (ECG). Using ECG and echocardiographic data, we developed deep learning and machine learning models to detect LVD and LVH. We also examined conventional ECG criteria for the diagnosis of LVH. We calculated the area under the receiver operating characteristic (AUROC) curve, sensitivity, specificity, and accuracy of each model and compared the performance of the models. We analyzed data for 18,954 patients (mean age (standard deviation): 64.2 (16.5) years, men: 56.7%). For the detection of LVD, the value (95% confidence interval) of the AUROC was 0.810 (0.801-0.819) for the deep learning model, and this was significantly higher than that of the logistic regression and random forest methods (P0.001). The AUROCs for the logistic regression and random forest methods (machine learning models) were 0.770 (0.761-0.779) and 0.757 (0.747-0.767), respectively. For the detection of LVH, the AUROC was 0.784 (0.777-0.791) for the deep learning model, and this was significantly higher than that of the logistic regression and random forest methods and conventional ECG criteria (P0.001). The AUROCs for the logistic regression and random forest methods were 0.758 (0.751-0.765) and 0.716 (0.708-0.724), respectively. This study suggests that deep learning is a useful method to detect LVD and LVH from 12-lead ECGs.

Aims Few studies have examined the relationship of blood pressure (BP) change in adults with elevated BP or stage 1 hypertension according to the American College of Cardiology (ACC)/American Heart Association (AHA) guideline with cardiovascular outcomes. We sought to identify the effect of BP change among individuals with elevated BP or stage 1 hypertension on incident heart failure (HF) and other cardiovascular diseases (CVDs). Methods and results We conducted a retrospective cohort study including 616 483 individuals (median age 46 years, 73.7% men) with elevated BP or stage 1 hypertension based on the ACC/AHA BP guideline. Participants were categorized using BP classification at one-year as normal BP (n = 173 558), elevated BP/stage 1 hypertension (n = 367 454), or stage 2 hypertension (n = 75 471). The primary outcome was HF, and the secondary outcomes included (separately) myocardial infarction (MI), angina pectoris (AP), and stroke. Over a mean follow-up of 1097 ± 908 days, 10 544 HFs, 1317 MIs, 11 070 APs, and 5198 strokes were recorded. Compared with elevated BP/stage 1 hypertension at one-year, normal BP at one-year was associated with a lower risk of developing HF [hazard ratio (HR): 0.89, 95% CI:0.85–0.94], whereas stage 2 hypertension at one-year was associated with an elevated risk of developing HF (HR:1.43, 95% CI:1.36–1.51). This association was also present in other cardiovascular outcomes including MI, AP, and stroke. The relationship was consistent in all subgroups stratified by age, sex, baseline BP category, and overweight/obesity. Conclusion A one-year decline in BP was associated with the lower risk of HF, MI, AP, and stroke, suggesting the importance of lowering BP in individuals with elevated BP or stage 1 hypertension according to the ACC/AHA guideline to prevent the risk of developing CVD.

Peer reviewed: True, Acknowledgements: We are grateful to all participants for their involvement., OBJECTIVES: We explored whether adapting neuropsychological tests for online administration during the COVID-19 pandemic was feasible for dementia research. DESIGN: We used a longitudinal design for healthy controls, who completed face-to-face assessments 3-4 years before remote assessments. For patients, we used a cross-sectional design, contrasting a prospective remote cohort with a retrospective face-to-face cohort matched for age/education/severity. SETTING: Remote assessments were conducted using video-conferencing/online testing platforms, with participants using a personal computer/tablet at home. Face-to-face assessments were conducted in testing rooms at our research centre. PARTICIPANTS: The remote cohort comprised 25 patients (n=8 Alzheimer's disease (AD); n=3 behavioural variant frontotemporal dementia (bvFTD); n=4 semantic dementia (SD); n=5 progressive non-fluent aphasia (PNFA); n=5 logopenic aphasia (LPA)). The face-to-face patient cohort comprised 64 patients (n=25 AD; n=12 bvFTD; n=9 SD; n=12 PNFA; n=6 LPA). Ten controls who previously participated in face-to-face research also took part remotely. OUTCOME MEASURES: The outcome measures comprised the strength of evidence under a Bayesian framework for differences in performances between testing environments on general neuropsychological and neurolinguistic measures. RESULTS: There was substantial evidence suggesting no difference across environments in both the healthy control and combined patient cohorts (including measures of working memory, single-word comprehension, arithmetic and naming; Bayes Factors (BF)01 >3), in the healthy control group alone (including measures of letter/category fluency, semantic knowledge and bisyllabic word repetition; all BF01 >3), and in the combined patient cohort alone (including measures of working memory, episodic memory, short-term verbal memory, visual perception, non-word reading, sentence comprehension and bisyllabic/trisyllabic word repetition; all BF01 >3). In the control cohort alone, there was substantial evidence in support of a difference across environments for tests of visual perception (BF01=0.0404) and monosyllabic word repetition (BF01=0.0487). CONCLUSIONS: Our findings suggest that remote delivery of neuropsychological tests for dementia research is feasible.

Funder: K.G.A. has received support from the American Heart Association Institute for Precision Cardiovascular Medicine (17IFUNP3384001), a KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from the Harvard Catalyst (KL2 TR002542), and the NIH (1K08HL153937)., Funder: B.N.W is supported by the National Science Foundation Graduate Research Program (DGE 1256260)., Funder: I.S. is supported by a Precision Health Scholars Award from the University of Michigan Medical School., Funder: I.K., S.Ko., and K.It. are funded by the Japan Agency for Medical Research and Development, AMED, under Grant Numbers JP16ek0109070h0003, JP18kk0205008h0003, JP18kk0205001s0703, JP20km0405209, and JP20ek0109487. The BioBank Japan is supported by AMED under Grant Number JP20km0605001., Funder: J.L.M.B. acknowledges research support from NIH R01HL125863, American Heart Association (A14SFRN20840000), the Swedish Research Council (2018-02529) and Heart Lung Foundation (20170265) and the Foundation Leducq (PlaqueOmics: Novel Roles of Smooth Muscle and Other Matrix Producing Cells in Atherosclerotic Plaque Stability and Rupture, 18CVD02., Funder: P.S.dV was supported by American Heart Association grant number 18CDA34110116 and National Heart, Lung, and Blood Institute grant R01HL146860. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research., Funder: O.G. has received funding from the British Heart Foundation (BHF) (FS/14/66/3129)., Funder: T.K. is supported by the Corona-Foundation (Junior Research Group Translational Cardiovascular Genomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02)., Funder: D.S.A. has received support from a training grant from the NIH (T32HL007604)., Funder: N.P.B., M.C.C., J.F., and D.-K.J. have been funded by the National Institute of Diabetes and Digestive and Kidney Diseases (2UM1DK105554)., Funder: A.V.K. has been funded by 1K08HG010155 from the National Human Genome Research Institute., Funder: C.P.N. and T.R.W received funding from the British Heart Foundation (SP/16/4/32697)., Funder: The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology; and Central Norway Regional Health Authority. Whole genome sequencing for the HUNT study was funded by HL109946., Funder: O.M. was funded by the Swedish Heart- and Lung Foundation, the Swedish Research Council, the European Research Council ERC-AdG-2019-885003 and Lund University Infrastructure grant ”Malmö population-based cohorts” (STYR 2019/2046)., Funder: This work was supported by the European Commission (HEALTH-F2–2013-601456) and the TriPartite Immunometabolism Consortium [TrIC]- NovoNordisk Foundation (NNF15CC0018486), VIAgenomics (SP/19/2/344612), the British Heart Foundation, a Wellcome Trust core award (M.F., H.W., 203141/Z/16/Z) and support from the NIHR Oxford Biomedical Research Centre. M.F. and H.W. are members of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health., Funder: J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator., Funder: J.C.H. acknowledges personal funding from the British Heart Foundation (FS/14/55/30806) and is a member of the Oxford BHF Centre of Research Excellence (RE/13/1/30181)., Funder: R.C. has received funding from the British Heart Foundation and British Heart Foundation Centre of Research Excellence., Funder: This research was supported by BHF (SP/13/2/30111) and conducted using the UK Biobank Resource (application number 9922)., Funder: The GerMIFs gratefully acknowledge the support of the Bavarian State Ministry of Health and Care, furthermore founded this work within its framework of DigiMed Bayern (grant No: DMB-1805-0001), the German Federal Ministry of Education and Research (BMBF) within the framework of ERA-NET on Cardiovascular Disease (Druggable-MI-genes: 01KL1802), within the scheme of target validation (BlockCAD: 16GW0198K), within the framework of the e:Med research and funding concept (AbCD-Net: 01ZX1706C), the British Heart Foundation (BHF)/German Centre of Cardiovascular Research (DZHK)-collaboration (VIAgenomics) and the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02) and the Sonderforschungsbereich SFB TRR 267 (B05)., Funder: C.J.W. is funded by NIH grant R35-HL135824., Funder: This work was supported by the British Heart Foundation (BHF) grant RG/14/5/30893 (P.D.) and forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR)., The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

Arterial structural and functional remodeling is recognized as a key determinant of incident heart failure, although the contribution of arterial properties on left ventricular (LV) remodeling is not fully studied. Aortic dilatation is an early manifestation of arterial remodeling and estimated pulse wave velocity (ePWV) is emerging as a simple measure of arterial stiffness. This study aimed to characterize the association of aortic size and ePWV with LV morphology and function.The study cohort consisted of 539 participants without overt cardiac disease who underwent extensive cardiovascular examination. Aortic root diameter was measured by two-dimensional echocardiography and ePWV was calculated from a regression equation using age and mean blood pressure. LV global longitudinal strain (LVGLS) was obtained by speckle-tracking echocardiography.Aortic root diameter and ePWV were correlated with LV mass index and LVGLS, while only ePWV was related to E / e' ratio. In multivariable analysis, aortic root diameter and ePWV were significantly related to LV mass index and LVGLS (all P 0.05), and the association of aortic root size and ePWV with LVGLS was independent of LV mass index and E / e' ratio. Individuals with both aortic root enlargement and increased ePWV had significantly larger LV mass index and reduced LVGLS compared with those either or those with normal aortic size and ePWV (both P 0.05).Aortic root size and ePWV were independently associated with unfavorable LV remodeling in individuals free of cardiac disease, which might provide useful information into the pathogenesis-linking arterial remodeling and heart failure.

Patients with COVID-19 and cardiovascular disease risk factors (CVDRF) have been reported to develop coagulation abnormalities frequently. However, there are limitations in conventional predictive models for the occurrence of thromboembolism in patients with COVID-19 and CVDRF.Among data on 1518 hospitalized patients with COVID-19 registered with CLAVIS-COVID, a Japanese nationwide cohort study, 693 patients with CVDRF were subjected to least absolute shrinkage and selection operator (LASSO) analysis; a method of shrinking coefficients for reducing variance and minimizing bias to increase predictive accuracy. LASSO analysis was performed to identify risk factors for systemic thromboembolic events; occurrence of arterial and venous thromboembolism during the index hospitalization as the primary endpoint.LASSO analysis identified a prior systemic thromboembolism, male sex, hypoxygenemia requiring invasive mechanical ventilation support, C-reactive protein levels and D-dimer levels at admission, and congestion on chest X-ray at admission as potential risk factors for the primary endpoint. The developed risk model consisting of these risk factors showed good discriminative performance (AUC-ROC: 0.83, 95 % confidence interval [CI]: 0.77-0.90), which was significantly better than that shown by D-dimer (AUC-ROC: 0.70, 95 % CI: 0.60-0.80) (p 0.001). Furthermore, systemic embolic events were independently associated with in-hospital mortality (adjusted odds ratio: 3.29; 95 % CI: 1.31-8.00).Six parameters readily available at the time of admission were identified as risk factors for thromboembolic events, and these may be capable of stratifying the risk of in-hospital thromboembolic events, which are associated with in-hospital mortality, in patients with COVID-19 and CVDRF.

Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies identified 130 distinct loci associated with at least one right heart measurement, of which 72 were not associated with left heart structures. Loci were found near genes previously linked with congenital heart disease, including NKX2-5, TBX5/TBX3, WNT9B and GATA4. A genome-wide polygenic predictor of right ventricular ejection fraction was associated with incident dilated cardiomyopathy (hazard ratio, 1.33 per standard deviation; P = 7.1 x 10(-13)) and remained significant after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic determinants of right heart structure and function.Genome-wide analyses of cardiac magnetic resonance imaging data identify loci associated with right heart structure and function. A polygenic predictor of right ventricular ejection fraction is associated with dilated cardiomyopathy risk.

In patients with type 2 diabetes mellitus (T2DM) without known cardiovascular disease, the association between B-type natriuretic peptide (BNP) and cardiovascular events except for heart failure has not been elucidated. We aimed to investigate this association in high-risk T2DM patients.We analyzed the association between BNP and cardiovascular events, including coronary, cerebral, renal, and vascular events or cardiovascular death based on the single and serial measurement of BNP in T2DM patients with retinopathy and hyperlipidemia without known cardiovascular disease enrolled in the EMPATHY study.Data from 4966 patients were analyzed for baseline BNP analysis. The median BNP value was 15.0 pg/mL. When analyzed in quartiles of baseline BNP (interquartile range 7.5-29.2 pg/mL), Q2, Q3, and Q4 were associated with cardiovascular events compared with Q1 (hazard ratio [HR]: Q2, 1.91 [P = 0.003]; Q3, 1.63 [P = 0.031]; Q4, 3.20 [P 0.001]). The analysis of 12-month BNP showed similar associations. In serial BNP measurement, compared with low-low BNP group (baseline ≤35 pg/mL and 12-month ≤35 pg/mL), low-high BNP group as well as high-high BNP group was associated with cardiovascular events (HR: low-high, 2.05 [P = 0.004]; high-high, 2.07 [P = 0.001]) and non-renal cardiovascular events. High-low BNP group tended to be associated with non-renal cardiovascular events (HR vs low-low: 2.05 [P = 0.056]).BNP levels were associated with first cardiovascular events except for heart failure in T2DM patients with retinopathy and hyperlipidemia. Serial BNP measurement may be useful in further stratifying high-risk patients among this T2DM population.

Asymptomatic or silent atrial fibrillation (AF) has long been a clinical problem due to the incidence of ischemic stroke. A method is needed to predict the development of silent AF before the occurrence of ischemic stroke. This study was focused on the symptoms of AF, especially palpitation, in pacemaker patients. We assessed the hypothesis that absence of palpitation during rapid ventricular pacing could be a predictor of future onset AF being asymptomatic.In this study, we assessed the presence of symptoms during RV pacing and AF symptoms on 145 pacemaker patients at the outpatient clinic by VVI pacing at 120 ppm. The relationship between symptoms during RV pacing and symptom during AF was assessed. The predictive value of absence of symptom during RV pacing on AF being asymptomatic was assessed.Of 145 patients, 74 had previous AF episode. Among the AF patients, absence of symptom during VVI pacing was associated with AF being asymptomatic.Of 145 patients, 71 had no previous AF events. There were 14 patients who had new-onset AF or atrial flutter (AFL) after the device implantation. Four of the 14 patients (28.6%) were symptomatic during first AF/AFL episode, and 10 (71.4%) were asymptomatic during first-onset AF. All ten patients who were asymptomatic during cardiac pacing test were asymptomatic during their initial episodes of AF as well.This study showed that absence of symptoms during rapid ventricular pacing was associated with first-onset AF being asymptomatic.

Agents targeting the programmed cell death-1 pathway have demonstrated encouraging activity across multiple solid tumor types. The dose expansion phase of this phase I study evaluated the safety, tolerability, and antitumor activity of durvalumab monotherapy, and durvalumab plus tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody) combination therapy, in patients from Asia with biliary tract cancer (BTC), esophageal squamous cell carcinoma (ESCC), or head and neck squamous cell carcinoma (HNSCC).Patients with advanced BTC, ESCC, or HNSCC with disease progression during or following ≥1 platinum-based therapy received durvalumab monotherapy (10 mg/kg every 2 weeks) or durvalumab plus tremelimumab (durvalumab 20 mg/kg every 4 weeks [Q4W] plus tremelimumab 1 mg/kg Q4W for 4 doses, followed by durvalumab 20 mg/kg Q4W). The primary objective was safety and tolerability. Secondary objectives included antitumor activity.Durvalumab monotherapy was assessed in 116 patients (median age 63.5 years, 75.9% male) of whom, 42, 42, and 32 had BTC, ESCC, or HNSCC, respectively. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 19.0%, 9.5%, and 25.0% of patients with BTC, ESCC, and HNSCC, respectively. Objective response rate (ORR) was 4.8%, 7.1%, and 9.4% in BTC, ESCC, and HNSCC. Durvalumab plus tremelimumab was evaluated in 124 patients (median age 62.0 years, 79.8% male) of whom 65 had BTC and 59 had ESCC. Grade ≥3 TRAEs were reported in 23.1% and 13.6% of patients with BTC and ESCC. ORR was 10.8% and 20.3% in BTC and ESCC. There were two complete responses and 10 partial responses in ESCC, and seven partial responses in BTC.In general, durvalumab monotherapy and durvalumab plus tremelimumab combination therapy displayed acceptable safety profiles consistent with published literature, and also demonstrated clinical benefit, in patients from Asia with BTC, ESCC, or HNSCC with disease progression on ≥1 prior treatment.gov Identifier: NCT01938612.

BACKGROUND Results of preceding studies on the relationship between blood pressure (BP) and cancers have been confounded due to individuals taking antihypertensive medications or shared risk factors. We assessed whether medication-naïve high BP is a risk factor for incident cancers. METHODS This retrospective observational study included 1,388,331 individuals without a prior history of cancer and not taking antihypertensive medications enrolled in the JMDC Claims Database between 2005 and 2018. The primary outcome was 16 cancers. RESULTS The median [interquartile range] age was 45 [40–52] years and 56.2% were men. Mean systolic BP (SBP) and diastolic BP (DBP) were 117.7 ± 15.8 and 72.8 ± 11.6 mm Hg. Multivariate Cox regression analysis demonstrated that SBP per 1-SD was associated with a higher incidence of thyroid (hazard ratio [HR]: 1.09, 95% confidence interval [CI]: 1.03–1.16), esophageal (HR: 1.15, 95% CI: 1.07–1.24), colorectal (HR: 1.04, 95% CI: 1.01–1.07), liver (HR: 1.11, 95% CI: 1.03–1.20), and kidney (HR: 1.22, 95% CI: 1.14–1.31) cancers, but with a lower incidence of stomach cancer (HR: 0.94, 95% CI: 0.91–0.98). These associations remained significant after adjustment for multiple testing. DBP was associated with higher incidences of thyroid, esophageal, colorectal, kidney, and corpus uteri cancers, but with a lower incidence of stomach cancer. The associations between SBP and incidences of thyroid, esophageal, colorectal, liver, and kidney cancers were confirmed in the Korean National Health Insurance Service database. CONCLUSIONS Medication-naïve BP was associated with higher incidences of thyroid, esophageal, colorectal, liver, and kidney cancers. Uncovering the underlying mechanisms for our results may help identify novel therapeutic approach for hypertension and cancer.

Ultrasound assessment of inferior vena cava (IVC) diameter and its respiratory variation is widely used to estimate right atrial pressure (RAP). Generally, the IVC distends as the RAP rises; however, there may be discrepancies between the values. Therefore, it is critical to recognize clinical factors other than RAP that may influence IVC measurements.We obtained the IVC maximum diameter and IVC collapsibility index (IVCCI) simultaneously during right-heart catheterization in 71 consecutive patients. Then, we assessed various clinical and hemodynamic factors to elucidate the independent determinants of IVC measurements. Moreover, we tried to generate the regression equation to estimate mean RAP from the IVC maximum diameter and IVCCI.The mean IVC maximum diameter and IVCCI were 15 ± 4 mm and 51 ± 15%, respectively. In stepwise multivariate analysis, the higher mean RAP (β = 0.52; p 0.0001), the presence of significant tricuspid regurgitation (β = 0.31; p = 0.0005), a larger body surface area (β = 0.22; p = 0.0017), and younger age (β = -0.18; p = 0.049) were independently associated with the IVC maximum diameter. Only the mean RAP was independently associated with the IVCCI (β = -0.45; p 0.0001). The regression equation (RDistension of the IVC mainly occurs with elevated RAP. However, the presence of significant tricuspid regurgitation, a larger body surface area, and younger age are associated with the IVC maximum diameter, independently of RAP. Interestingly, IVCCI is influenced only by RAP.

Context The natural history of young adults with prediabetes and its association with cardiovascular health (CVH) metrics in progression to diabetes remain unknown. Objective We examined the association between CVH metrics and the annual incidence of diabetes in young adults with prediabetes. Methods This observational cohort study used the JMDC Claims Database. We analyzed 18 908 participants aged 18 to 44 years, with available fasting plasma glucose (FPG) data for 5 consecutive years, and who had prediabetes (FPG 100-125 mg/dL) at the initial health checkup. The ideal CVH metrics were as follows: nonsmoking, body mass index (BMI) less than 25 kg/m2, physical activity at goal, optimal dietary habits, blood pressure less than 120/80 mm Hg, and total cholesterol less than 200 mg/dL. We analyzed the association between CVH metrics and the annual incidence of diabetes. We also examined the relationship between 1-year changes in CVH metrics and the subsequent risk of diabetes. Results The incidence of diabetes was 3.3% at 1 year and 9.5% at 5 years after the initial health checkup. An increasing number of nonideal CVH metrics have been associated with an increased risk of diabetes. Nonideal BMI, smoking, blood pressure, and total cholesterol level were associated with an increased risk of diabetes. This association was observed both in men and women. A one-point increase in the number of nonideal CVH metric components was associated over 1 year with an increased risk of diabetes. Conclusion CVH metrics can stratify the risk of diabetes in young adults with prediabetes. Improving CVH metrics may reduce the risk of developing diabetes.

Whether blood pressure (BP) classification using the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) BP guideline can identify patients at high risk for proteinuria remains unknown. We examined the association of BP classification using the 2017 ACC/AHA guideline with the subsequent risk for the development of proteinuria. This is an observational cohort study using the JMDC Claims Database. We analyzed 914,786 participants with negative proteinuria assessed using urine dipstick tests at the initial health check-ups, not taking BP-lowering medications, and who underwent repeated urine dipstick tests within 4 years. Based on the 2017 ACC/AHA guideline, each participant was categorized as having normal BP (n = 487,020), elevated BP (n = 134,798), stage 1 hypertension (n = 197,618), or stage 2 hypertension (n = 95,350). The primary outcome was incident proteinuria. We investigated the association of BP based on the 2017 ACC/AHA guideline category with incident proteinuria using multivariable analyses. We used restricted cubic spline functions to identify the relation between systolic BP (SBP) and the risk for proteinuria. The median age was 45 years, and 59.4% were men. Multivariable analysis demonstrated that stage 1 hypertension (relative risk 1.14, 95% confidence interval 1.11 to 1.17), and stage 2 hypertension (relative risk 1.48, 95% confidence interval 1.43 to 1.52) were associated with a higher incidence of proteinuria than normal BP. The restricted cubic spline demonstrated that the risk for proteinuria increased linearly with SBP after SBP exceeded 120 mm Hg. Not only stage 2 hypertension but also stage 1 hypertension was associated with a greater risk for proteinuria, suggesting the importance of establishing the management strategy for stage 1 hypertension.

Dilated cardiomyopathy (DCM) is caused by various gene variants and characterized by systolic dysfunction. Lamin variants have been reported to have a poor prognosis. Medical and device therapies are not sufficient to improve the prognosis of DCM with the lamin variants. Recently, induced pluripotent stem (iPS) cells have been used for research on genetic disorders. However, few studies have evaluated the contractile function of cardiac tissue with lamin variants. The aim of this study was to elucidate the function of cardiac cell sheet tissue derived from patients with lamin variant DCM. iPS cells were generated from a patient with lamin A/C (LMNA) -mutant DCM (LMNA p.R225X mutation). After cardiac differentiation and purification, cardiac cell sheets that were fabricated through cultivation on a temperature-responsive culture dish were transferred to the surface of the fibrin gel, and the contractile force was measured. The contractile force and maximum contraction velocity, but not the maximum relaxation velocity, were significantly decreased in cardiac cell sheet tissue with the lamin variant. A qRT-PCR analysis revealed that mRNA expression of some contractile proteins, cardiac transcription factors, Ca

The Japan Circulation Society launched the STOP-MI campaign in 2014, focusing on immediate hospital arrival for acute myocardial infarction (AMI) treatment. This study aimed to determine the factors influencing longer prehospital time among patients with AMI in Japan.Methods and Results:This study analyzed a total of 4,625 AMI patients enrolled in the Osaka Acute Coronary Insufficiency Study registry from 1998 to 2014. The prehospital time delay was defined as the time interval from the onset of initial symptoms to hospital arrival time ≥2 h. Among eligible patients, 2,927 (63.3%) had a prehospital time ≥2 h. In multivariable analyses, age 65-79 years (adjusted odds ratio [AOR] 1.19, 95% confidence interval [CI] 1.02-1.39), age ≥80 years (AOR 1.42, 95% CI 1.13-1.79), diabetes mellitus (AOR 1.33, 95% CI 1.16-1.52), and onset time of 0:00-5:59 h (AOR 1.63, 95% CI 1.37-1.95) were positively associated with prehospital time ≥2 h, whereas smoking (AOR 0.78, 95% CI 0.68-0.90) and ambulance use (AOR 0.37, 95% CI 0.32-0.43) were negatively associated with prehospital time ≥2 h.Older age, diabetes mellitus, and nighttime onset were associated with prehospital time delay for AMI patients, whereas smoking and ambulance use were associated with no prehospital time delay. Healthcare providers and patients could help reduce the time to get to a medical facility by being aware of these findings.

BACKGROUND Aortic regurgitation (AR) is a common heart disease, with a relatively high prevalence of 4.9% in the Framingham Heart Study. Because the prevalence increases with advancing age, an upward shift in the age distribution may increase the burden of AR. To provide an effective screening method for AR, we developed a deep learning-based artificial intelligence algorithm for the diagnosis of significant AR using electrocardiography (ECG). METHODS Our dataset comprised 29,859 paired data of ECG and echocardiography, including 412 AR cases, from January 2015 to December 2019. This dataset was divided into training, validation, and test datasets. We developed a multi-input neural network model, which comprised a two-dimensional convolutional neural network (2D-CNN) using raw ECG data and a fully connected deep neural network (FC-DNN) using ECG features, and compared its performance with the performances of a 2D-CNN model and other machine learning models. In addition, we used gradient-weighted class activation mapping (Grad-CAM) to identify which parts of ECG waveforms had the most effect on algorithm decision making. RESULTS The area under the receiver operating characteristic curve of the multi-input model (0.802; 95% CI, 0.762-0.837) was significantly greater than that of the 2D-CNN model alone (0.734; 95% CI, 0.679-0.783; p

Respiratory infections are common, and the most common causative agent is a virus. Therefore, routine surveillance of respiratory viruses is useful in the case of novel viral diseases such as coronavirus disease 2019 (COVID-19). In this study, to clarify the kind of virus involved in suspected cases of COVID-19 in the early stages of the pandemic, we attempted to detect various respiratory viruses in 613 specimens that tested negative for severe acute respiratory syndrome coronavirus 2 using reverse transcription polymerase chain reaction. As a result, viruses were detected in 59 (9.6%) patients. In addition, human rhinovirus (HRV), human metapneumovirus (HMPV), human respiratory syncytial virus, and human parechovirus were detected in 29, 25, 3, and 2 patients, respectively. Although this study was conducted over a short period of time and not all specimens were tested, these results indicate that various respiratory viruses, especially HRV and HMPV, can be detected even during the early stages of the COVID-19 pandemic. Because various respiratory viruses maintain a constant effect during the outbreak of the newly emerged pandemic, systematic surveillance of respiratory viruses is needed during the normal period to make good use for clinical and public health.

The impact of blood pressure (BP) levels on subclinical left ventricular (LV) dysfunction and possible sex-specific difference remains unclarified. This study investigated the relationship between BP categories given in the new 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline and subclinical LV dysfunction in subjects free of cardiac disease.We examined antihypertensive medication-naive 858 individuals who underwent extensive cardiovascular health check-up. LV global longitudinal (LVGLS) and circumferential strain (LVGCS) were assessed by two-dimensional speckle-tracking echocardiography. Participants were categorized into four groups: normal BP, elevated BP, isolated diastolic hypertension (IDH), and systolic hypertension (SH). Among the 858 participants, 422 individuals had normal BP, 113 had elevated BP, 160 had IDH, and 163 had SH. Prevalence of abnormal LVGLS (-18.6%) was greatest in SH (19.0%), followed by IDH (17.5%), elevated BP (14.2%), and normal BP (7.1%, P 0.001); no significant differences were observed for LVGCS (P = 0.671). In the multivariable analyses, IDH and SH were associated with impaired LVGLS [adjusted odds ratio (OR) 2.69 and 2.66, P 0.001], and borderline significance was observed for elevated BP (adjusted OR 1.90, P = 0.060); there was no significant association between any of the BP groups and LVGCS. In sex-stratified analysis, IDH and SH carried the significant risk of abnormal LVGLS in both sexes, while elevated BP was associated with LVGLS only in women.Isolated diastolic hypertension and SH redefined by ACC/AHA guideline carried significant risk for LVGLS, but not LVGCS. Elevated BP was associated with LVGLS only in women. Our findings provide information on cardiac correlates of the newly established BP categories.

Heart transplantation (HT) is an effective therapeutic option for end-stage heart failure. Infection is a major cause of morbidity and mortality after HT. Sarcopenia, defined as the loss of muscle mass and strength, is a common comorbidity in HT candidates with end-stage heart failure. However, the effects of sarcopenia on the occurrence of post-HT infections are not well understood. Therefore, we explored the association between the skeletal muscle mass and post-transplant infections in adult HT recipients.We retrospectively examined the records of 135 patients who underwent HT between August 2007 and November 2019 at our institution. Pre-transplant computed tomography was used to calculate the skeletal muscle index (SMI) at the level of the third lumbar vertebra. Muscle wasting was defined as the SMI of the lowest sex-based tertiles. The primary endpoint was infections within 6 months of HT. The study included 109 patients (80 men, mean age: 41.6 ± 12.0 years): 37 patients in the muscle wasting group and 72 patients in the non-muscle wasting group. The mean SMI values in the muscle wasting and non-muscle wasting groups were 29.9 ± 4.8 cmLow skeletal muscle mass is a predictor of post-HT infections within 6 months of HT.

The prognostic significance of combining intra-aortic balloon pumping (IABP) with extracorporeal membrane oxygenation (ECMO) for acute myocardial infarction (AMI) patients is still unclear. We investigated whether combining IABP with veno-arterial (VA)-ECMO is associated with a lower risk of short-term mortality.Among 12,093 AMI cases enrolled in the Osaka Acute Coronary Insufficiency Study (OACIS), we identified 519 who were administered VA-ECMO during hospitalization. Among these, 459 received IABP support (IABP group) and 60 cases did not (no-IABP group). The primary endpoint was 30-day all-cause death; the secondary endpoint was major bleeding. Logistic regression analysis using original data was conducted. We also established weighted logistic regression models with inverse probability of treatment weighting (IPTW).Logistic regression analysis revealed that IABP use was significantly associated with a reduced risk of 30-day death in the original data [odds ratio (OR) 0.504, 95% confidence interval (CI) 0.282-0.901, p = 0.021]. After IPTW-adjustment for clinically relevant covariates with the use of IABP, patients receiving VA-ECMO with IABP had a lower risk of 30-day death (OR 0.816, 95% CI 0.746-0.892, p0.001) compared to those without IABP. The incidence of major bleeding was comparable between the groups (IABP 29.0% vs. non-IABP 21.7%, p=0.302). However, the risk of major bleeding was higher in the IABP group after IPTW-adjustment (OR 1.092, 95% CI 1.008-1.184, p=0.032).IABP support for AMI patients with VA-ECMO was significantly associated with reduced risk of short-term mortality, suggesting that the addition of IABP support might contribute to improved survival in AMI patients requiring VA-ECMO.

ImportanceThe clinical utility of polygenic risk scores (PRS) for coronary artery disease (CAD) has not yet been established.ObjectiveTo investigate the ability of a CAD PRS to potentially guide statin initiation in primary prevention after accounting for age and clinical risk.Design, Setting, and ParticipantsThis was a longitudinal cohort study with enrollment starting on January 1, 2006, and ending on December 31, 2010, with data updated to mid-2021, using data from the UK Biobank, a long-term population study of UK citizens. A replication analysis was performed in Biobank Japan. The analysis included all patients without a history of CAD and who were not taking lipid-lowering therapy. Data were analyzed from January 1 to June 30, 2022.ExposuresPolygenic risk for CAD was defined as low (bottom 20%), intermediate, and high (top 20%) using a CAD PRS including 241 genome-wide significant single-nucleotide variations (SNVs). The pooled cohort equations were used to estimate 10-year atherosclerotic cardiovascular disease (ASCVD) risk and classify individuals as low (Main Outcomes and MeasuresMyocardial infarction (MI) and ASCVD events (defined as incident clinical CAD [including MI], stroke, or CV death).ResultsA total of 330 201 patients (median [IQR] age, 57 [40-74] years; 189 107 female individuals [57%]) were included from the UK Biobank. Over the 10-year follow-up, 4454 individuals had an MI. The CAD PRS was significantly associated with the risk of MI in all age groups but had significantly stronger risk prediction at younger ages (age 60 years: HR, 1.42; 95% CI, 1.37-1.48; P for interaction Conclusions and RelevanceResults of this cohort study suggest that the predictive ability of a CAD PRS was greater in younger individuals and can be used to better identify patients with borderline and intermediate clinical risk who should initiate statin therapy.

Background Hypertension and diabetes frequently coexist. However, little is known about the interaction between high blood pressure (BP) and hyperglycemia in the development of cardiovascular disease (CVD). Methods and Results We conducted an observational cohort study that included 3 336 363 patients (median age, 43 years old; men, 57.2%). People taking BP‐ or glucose‐lowering medications or those with prior history of CVD were excluded. We defined stage 1 hypertension as having systolic BP of 130 to 139 mm Hg or diastolic BP of 80 to 89 mm Hg and stage 2 hypertension as having systolic BP of ≥140 mm Hg or diastolic BP of ≥90 mm Hg. We defined prediabetes as having fasting plasma glucose of 100 to 125 mg/dL and diabetes as having fasting plasma glucose of ≥126 mg/dL. Over a mean follow‐up period of 1185 ± 942 days, 5665 myocardial infarction, 52 475 angina pectoris, 25 436 stroke, 54 508 heart failure, and 12 932 atrial fibrillation events occurred. The BP and fasting plasma glucose categories additively increased the risk of myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. However, the relative risk of stage 1 and stage 2 hypertension developing into CVD was attenuated with deteriorating glycemic status. Similarly, the relative risk of prediabetes and diabetes developing into CVD was attenuated with increasing BP. For example, the relative risk reduction of stage 2 hypertension for heart failure was 53.5% in individuals with normal fasting plasma glucose, 46.4% in those with prediabetes, and 37.2% in those with diabetes. The robustness of our findings was confirmed using a multitude of sensitivity analyses. Conclusions Although hypertension and hyperglycemia additively increase the risk of developing CVD, the relative contribution of hypertension to the development of CVD decreased with deteriorating glycemic status and that of hyperglycemia was attenuated with increasing BP. Our results indicate a potential interaction between hypertension and hyperglycemia in the development of CVD.

PURPOSE Lid wiper epitheliopathy (LWE) is an epitheliopathy of the marginal conjunctival portion of the eyelids that wipes the ocular surface during blinking. Although LWE is often observed in patients with dry eye, the factors determining LWE severity in dry eye remain unknown. Therefore, we investigated the relationship between LWE, tear abnormalities, and blinks in dry eye. METHODS This study involved 76 eyes of 76 female patients with dry eye (mean age: 57.2 yrs). In all eyes, tear meniscus radius, spread grade (SG) of the tear film lipid layer (ie, SG 1-5, with 1 being the best), fluorescein breakup time (FBUT), fluorescein breakup pattern, corneal and bulbar conjunctival epithelial damage (CED: 15 points maximum; CjED: 6 points maximum, respectively), upper eyelid LWE grade (3 points maximum), and Schirmer 1 test were evaluated. Blink rate, palpebral aperture height, upper eyelid opening/closing-phase amplitude, upper eyelid opening/closing-phase duration, and upper eyelid opening/closing-phase maximum velocity were measured by the use of a custom-made high-speed blink analyzer. Finally, the factors that determine the LWE grade were investigated by multiple regression analysis, in which the parameters were chosen using the stepwise procedure. RESULTS Significant correlations were found between LWE grade and tear meniscus radius, SG, FBUT, CED, CjED, and Schirmer 1 test (P < 0.002). LWE grade was found to be described as -0.001 + (0.283 × SG) - (0.253 × FBUT) + (0.003 × upper eyelid closing-phase maximum velocity) (R2 = 0.57, P < 0.0001). The prevalence and grade of LWE were significantly higher in aqueous deficient dry eye. CONCLUSIONS Tear volume, tear film stability, and blink should be considered as factors for determining LWE severity.

Background Extensive data support the clinical benefit of cardiac rehabilitation (CR) for patients with chronic heart failure (HF). However, whether CR could be beneficial for patients hospitalized for acute heart failure remains unclear. Methods We retrospectively analyzed data from the Diagnosis Procedure Combination database, a nationwide inpatient database. We included patients hospitalized for HF, who were aged ≥20 years and with New York Heart Association class ≥II, between January 2010 and March 2018. We excluded patients with length of hospital stay ≤2 days, those undergoing major procedures under general anesthesia, those requiring advanced mechanical supports within 2 days after admission, and those with disturbance of consciousness. Propensity score matching and instrumental variable analyses were conducted to compare clinical outcomes between the patients with and without acute-phase initiation of CR defined as initiation of CR within two days after hospital admission. Results Among 430,216 eligible patients, 63,470 patients (14.8%) received the acute-phase initiation of CR. Propensity score matching created 63,470 pairs and found that the acute-phase initiation of CR was associated with lower in-hospital mortality (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.73–0.80), shorter hospital stay and lower incidence of 30-day readmission due to HF. The instrumental variable analysis also showed patients with acute-phase initiation of CR was associated with lower in-hospital mortality than those without (OR, 0.73; 95% CI, 0.68–0.79). Conclusion Our analysis suggested a potential benefit of acute-phase initiation of CR for short-term clinical outcomes in hospitalized patients with acute HF.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease with obstructed airflow and frequently causes secondary mild-moderate pulmonary hypertension (PH). However, a low proportion (1%-5%) of COPD patients develop severe therapy-resistant PH, and it is crucial to determine whether the patient has another disease capable of causing severe PH, including pulmonary arterial hypertension.Here, we describe a case of a 71-year-old male with COPD complicated by severe PH and right heart failure. He had a history of heavy smoking and developed progressive hypoxemia on exertion. He had severe airflow limitation (forced expiratory volume % in one second, FEV 1.0% = 42.8%) with a markedly reduced diffusing capacity of the lung (predicted diffusion capacity of carbon monoxide, %DLCO = 29%), and high-resolution computed tomography (CT) demonstrated significant lung parenchymal abnormalities such as diffuse interlobular septal thickening, ground-glass opacities, and enlarged mediastinal lymph nodes. He was diagnosed with group 3 PH caused by COPD but resistant to the treatment of COPD, diuretics, and oxygen therapy. Pathohistological analysis of autopsy specimens revealed the coexistence of interstitial fibrosis and partial occlusion of the small intrapulmonary veins, which led to a conclusive diagnosis of pulmonary veno-occlusive disease (PVOD).Because of its rarity and similarity with idiopathic pulmonary arterial hypertension, PVOD is difficult to diagnose antemortem and has a poor prognosis. High-resolution CT findings (septal thickening, ground glass, and enlarged lymph nodes) and severely reduced DLCO should be carefully evaluated for the early detection and treatment of PVOD in COPD patients with severe PH.

BACKGROUND The risk of developing hypertension in young adults and its relationship to modifiable lifestyle factors are unclear. We aimed to examine the association of cardiovascular health (CVH) metrics with the risk of hypertension. METHODS We analyzed 66,876 participants aged 20–39 years, with available blood pressure (BP) data for 5 consecutive years, who had normal or elevated BP at the initial health check-up, enrolled in the JMDC Claims Database. Ideal CVH metrics included nonsmoking, body mass index RESULTS The median age was 35 years, and 62% were men. Number of non-ideal CVH metrics was associated with an increasing risk for the development of stage 1 and stage 2 hypertension. Non-ideal body mass index was most strongly associated with a risk for hypertension. This association was more pronounced in women. An annual increase in the number of non-ideal CVH metrics was associated with an elevated risk for the hypertension development. CONCLUSIONS CVH metrics can stratify the risk for hypertension in non-hypertensive adults aged 20–39 years. These findings have important public health implications for the screening and prevention of hypertension. Improving CVH metrics may prevent the risk of developing hypertension in young adults.

Background Large multicenter studies reporting on the association between the duration of broad-spectrum antimicrobial administration and the detection of multidrug-resistant (MDR) bacteria in the intensive care unit (ICU) are scarce. We evaluated the impact of broad-spectrum antimicrobial therapy for more than 72 h on the detection of MDR bacteria using the data from Japanese patients enrolled in the DIANA study. Methods We analyzed the data of ICU patients in the DIANA study (a multicenter international observational cohort study from Japan). Patients who received empirical antimicrobials were divided into a broad-spectrum antimicrobial group and a narrow-spectrum antimicrobial group, based on whether they received broad-spectrum antimicrobials for more or less than 72 h, respectively. Differences in patient characteristics, background of infectious diseases and empirical antimicrobial administration, and outcomes between the two groups were compared using the chi-square tests (Monte Carlo method) for categorical variables and the Mann–Whitney U-test for continuous variables. We also conducted a logistic regression analysis to investigate the factors associated with the detection of new MDR bacteria. Results A total of 254 patients from 31 Japanese ICUs were included in the analysis, of whom 159 (62.6%) were included in the broad-spectrum antimicrobial group and 95 (37.4%) were included in the narrow-spectrum antimicrobial group. The detection of new MDR bacteria was significantly higher in the broad-spectrum antimicrobial group (11.9% vs. 4.2%, p = 0.042). Logistic regression showed that broad-spectrum antimicrobial continuation for more than 72 h (OR [odds ratio] 3.09, p = 0.047) and cerebrovascular comorbidity on ICU admission (OR 2.91, p = 0.041) were associated with the detection of new MDR bacteria. Conclusions Among Japanese ICU patients treated with empirical antimicrobials, broad-spectrum antimicrobial usage for more than 72 h was associated with the increased detection of new MDR bacteria. Antimicrobial stewardship programs in ICUs should discourage the prolonged use of empirical broad-spectrum antimicrobial therapy. Trial registration ClinicalTrials.gov, NCT02920463, Registered 30 September 2016, https://clinicaltrials.gov/ct2/show/NCT02920463

Background With aging population, the prevalence and incidence of heart failure (HF) have been increasing worldwide. However, the characteristics and outcomes of patients with HF in an era of aging are not well established in Japan.Methods and Results:The Japanese Registry Of Acute Decompensated Heart Failure (JROADHF), a retrospective, multicenter, nationwide registry, was designed to study the clinical characteristics and outcomes of patients hospitalized with HF throughout Japan in 2013. One hundred and twenty-eight hospitals were selected by cluster random sampling and 13,238 hospitalized patients with HF were identified by medical record review. Demographics, medical history, severity, treatment, and in-hospital and long-term outcome data were collected from the Diagnostic Procedure Combination and medical charts. Data were analyzed using univariate and multivariate logistic regression or Cox regression analysis. The mean age of registered patients was 78.0±12.5 years and 52.8% were male. Elderly patients (age >75 years) accounted for 68.9%, and HF with preserved ejection fraction (HFpEF) accounted for 45.1%. Median length of hospital stay was 18 days and in-hospital mortality was 7.7%. The median follow-up period was 4.3 years, and the incidence rates for cardiovascular death and rehospitalization for HF were 7.1 and 21.1 per 100 person-years, respectively. Conclusions A contemporary nationwide registry demonstrated that hospitalized HF patients were very elderly, HFpEF was common, and their prognosis was still poor in Japan.

Aims Although comprehensive assessment of right ventricular (RV) function using multiple echocardiographic parameters is recommended for management of patients with non‐ischaemic dilated cardiomyopathy (DCM), it is unclear which RV parameters to combine. Additionally, normalization of RV parameters by estimated pulmonary artery systolic pressure (PASP), in consideration of RV–pulmonary artery coupling, may be clinically significant. The aim of our study was to elucidate the best combination of echocardiographic RV functional parameters, with or without indexing for PASP, to predict outcome in patients with heart failure with reduced ejection fraction secondary to DCM. Methods and results We retrospectively analysed 109 DCM patients with left ventricular ejection fraction −8.6%) had significantly higher hazard ratio than those with either impairment alone (11.3 vs. 3.4, P

Serum uric acid (SUA) was reported to be associated with incident cardiovascular disease (CVD). However, the relationship between SUA and CVD among young adults has not been clarified yet. In this study, we aimed to identify the association of medication naive SUA with incident CVD including myocardial infarction (MI), stroke, heart failure (HF) and atrial fibrillation (AF) using a nationwide epidemiological database. We analyzed 353,613 participants aged 20-49 years, who were not taking UA lowering medications, and had no prevalent history of cardiovascular disease (CVD) using a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2018. Median [interquartile range] age was 40 [34-44] years, and 46.9% were men. Over a mean follow-up of 1,176±876 days, 391 (0.1%) incident MI, 1,308 (0.4%) incident stroke, 3,374 (1.0%) incident HF, and 684 (0.2%) incident AF events occurred. Kaplan-Meier curves and the log-rank test showed that there was a significant difference in incident MI, stroke, HF, and AF among the groups based on SUA tertile (all log-rank p< 0.001). Multivariable Cox regression analysis showed that the upper tertile of SUA (SUA ≥ 5.7 mg/dL) was associated with higher incidence of MI (HR 1.45, 95% CI 1.00-2.10), HF (HR 1.13, 95% CI 1.01-1.28), and AF (HR 1.35, 95% CI 1.02-1.78) compared with the first tertile of SUA (SUA < 4.4 mg/dL). SUA as continuous variable was independently associated with incident MI (HR 1.10, 95% CI 1.00-1.20), stroke (HR 1.06, 95% CI 1.00-1.11), HF (HR 1.07, 95% CI 1.03-1.10), and AF (HR 1.11, 95% CI 1.04-1.19). SUA ≥ 7.0 mg/dL was independently associated with incident HF (HR 1.24, 95% CI 1.12-1.38). In conclusion, higher SUA was associated with increased incidence of CVD events in individuals aged< 50 years, suggesting the potential significance of the optimal UA control for the primary CVD prevention even in young adults.

Glioma‐initiating cells (GICs), a major source of glioblastoma recurrence, are characterized by the expression of neural stem cell markers and the ability to grow by forming nonadherent spheres under serum‐free conditions. Bone morphogenetic proteins (BMPs), members of the transforming growth factor‐β family, induce differentiation of GICs and suppress their tumorigenicity. However, the mechanisms underlying the BMP‐induced loss of GIC stemness have not been fully elucidated. Here, we show that paired related homeobox 1 (PRRX1) induced by BMPs decreases the CD133‐positive GIC population and inhibits tumorigenic activity of GICs in vivo. Of the two splice isoforms of PRRX1, the longer isoform, pmx‐1b, but not the shorter isoform, pmx‐1a, induces GIC differentiation. Upon BMP stimulation, pmx‐1b interacts with the DNA methyltransferase DNMT3A and induces promoter methylation of the PROM1 gene encoding CD133. Silencing DNMT3A maintains PROM1 expression and increases the CD133‐positive GIC population. Thus, pmx‐1b promotes loss of stem cell‐like properties of GICs through region‐specific epigenetic regulation of CD133 expression by recruiting DNMT3A, which is associated with decreased tumorigenicity of GICs., BMPs induce differentiation and apoptosis of glioma‐initiating cells (GICs). Here, we identified PRRX1 as a target of BMPs in GICs. Of the two splice isoforms, only pmx‐1b induced GIC differentiation. Through interaction with DNMT3A, pmx‐1b induced the methylation of the PROM1 gene promoter and suppressed the CD133+ GIC population. Thus, site‐specific epigenetic regulation plays a critical role in the differentiation of GICs.

Parallel connection of an electrophysiology recording system (EP system) to equipment for conduction system pacing (CSP) has been widely used for fine monitoring of intracardiac electrograms and pacing evaluation. We experienced a case showing unexpected pacing threshold exacerbation under specific conditions when the EP system was connected in parallel. We evaluated the underlying mechanism using an ex vivo model. An ex vivo pacing and intracardiac electrogram monitoring model was generated using an oscilloscope, pacing system analyzer (PSA), EP system, and simulated heart. The discrepancy between expected output at the PSA and the actual measured output value at the simulated heart was measured under various conditions and using various combinations of pacing equipment. Parallel connection of the EP system was associated with reduced electrical output from the PSA as recorded at the simulated heart. The unexpected adverse effects were particularly noticeable when using an RMC-5000 EP system with the pacing function on. The trouble is completely resolved by simply turning off the pacing function of the system. There is a possibility that the EP system might increase the pacing threshold in CSP when the PSA and EP system is are deployed in parallel. The issue may provoke pseudo failure of CSP due to the high pacing threshold. When the RMC-5000 is used for conduction system pacing in parallel with a PSA for the pacing test, the pacing function of RMC-5000 should be turned off.

Aims/Introduction As estimated glomerular filtration rate (eGFR) progression might correlate with cardiovascular prognosis, the correlation between 1‐year decline in eGFR and cardiovascular incidences and renal outcome was investigated. Materials and Methods The 1‐year percentage decline in eGFR at the first observation year was calculated in a cohort of the standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) trial participants. The primary end‐point was the composite cardiovascular end‐point including the renal end‐point. The associations between the incidence of each end‐point and clinical markers were analyzed using the Cox proportional hazards regression model. Results A total of 4,461 patients were analyzed. The mean observation period was 765.3 ± 363.1 days. The best cut‐off value of 1‐year eGFR decline was 0.099 in the first year for renal end‐point prediction by receiver operating characteristic curve analysis. The area under the curve of the model including the 1‐year eGFR decline of the first year was significantly larger than the model without it (0.943, 95% confidence interval 0.915–0.971 to 0.967, 95% confidence interval 0.950–0.983, P = 0.019). Primary end‐point incidences and the renal end‐point were much higher in rapid eGFR decliners compared with non‐decliners (P, Primary end‐point incidences and renal end‐point were much higher in rapid estimated glomerular filtration rate decliners compared with non‐decliners (P

Aims/Introduction Long‐term glycemic variability is important for predicting diabetic complications, but evaluation in a Japanese population is lacking. The aim of this study was to explore the relationship between visit‐to‐visit glycemic variability (VVV) and cardiovascular diseases (CV) in Japanese patients with type 2 diabetes, using the prospective cohort of the EMPATHY trial. Materials and Methods Among 4532 participants with at least three HbA1c measurements, VVV was defined using the coefficient of variation (CV‐HbA1c). The outcomes were the composite cardiovascular endpoints, including cardiac, cerebral, renal, and vascular events. The odds ratios (ORs) for the development of outcomes were estimated by using logistic regression models. Results During a median follow‐up of 38 months, 190 subjects developed CV events. The risk of developing CV events increased significantly with increasing quintile of CV‐HbA1c, after multivariable adjustment including the mean‐HbA1c (OR for the fifth vs first quintile, 1.73; 95%CI, 1.03–2.91; P for trend test = 0.003). There was a stronger association between CV‐HbA1c and CV events in patients with a mean‐HbA1c of, The long‐term variability of HbA1c as well as the mean HbA1c might be an important glycemic indicator in the management of patients with type 2 diabetes, especially in those with a mean‐HbA1c of

Statin therapy may decrease the levels of serum steroid hormones, including testosterone and cortisol, accompanied by lowering low-density lipoprotein cholesterol (LDL-C) levels, which remains to be investigated. The aim of this study is to examine the association between steroid hormones and lipids under statin therapy and its clinical impact on the cardiovascular event risk from a viewpoint of steroid hormone metabolism. Using a population dataset extracted from the standard versus intEnsive statin therapy for hyper-cholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study, we analyzed the correlation between steroid hormones and lipid profiles at registration and 1 year after registration, comparing between male patients with or without cardiovascular events (CV events) within 4 years (CV events + ; n = 100, and CV events − ; n = 100, respectively) after prognostic score matching. The risk for CV events was evaluated using conditional logistic regression analysis. Testosterone levels were lower in the CV events + group than in the CV events − group at registration (5.2 ± 2.2 vs. 7.6 ± 4.1 ng/mL, p

Background Obesity and metabolic disorders frequently coexist, and both are established risk factors for cardiovascular disease (CVD). Although the phenotype of obesity without metabolic disorders, referred to as metabolically healthy obesity (MHO), is attracting clinical interest, the pathophysiological impact of MHO remains unclear.Methods and Results:Using the Japan Medical Data Center database, we studied 802,288 subjects aged ≥20 years without any metabolic disorders or a prior history of CVD. MHO, defined as obesity (body mass index ≥25 kg/m2) with no metabolic disorders, was observed in 9.8% of the study population. The subjects' mean (±SD) age was 42.8±9.4 years and 44.7% were men. The mean follow-up period was 1,126±849 days. Multivariable Cox regression analysis showed that MHO alone did not significantly increase the risk of any CVD. However, abdominal obesity alone increased the risk of heart failure and atrial fibrillation. Moreover, the coexistence of MHO and abdominal obesity increased the risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation. The incidence of stroke was not associated with the presence of MHO and abdominal obesity. Conclusions Among individuals with no metabolic disorders, MHO alone did not significantly increase the subsequent CVD risk. However, individuals with comorbid MHO and abdominal obesity had a higher risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation, suggesting the prognostic importance of abdominal obesity in subjects with MHO.

BACKGROUND: Cardiovascular diseases and/or risk factors (CVDRF) have been reported as risk factors for severe coronavirus disease 2019 (COVID-19).Methods and Results:In total, we selected 693 patients with CVDRF from the CLAVIS-COVID database of 1,518 cases in Japan. The mean age was 68 years (35% females). Statin use was reported by 31% patients at admission. Statin users exhibited lower incidence of extracorporeal membrane oxygenation (ECMO) insertion (1.4% vs. 4.6%, odds ratio [OR]: 0.295, P=0.037) and septic shock (1.4% vs. 6.5%, OR: 0.205, P=0.004) despite having more comorbidities such as diabetes mellitus. CONCLUSIONS: This study suggests the potential benefits of statins use against COVID-19.

BACKGROUND Intensive lipid-lowering therapy is recommended in type 2 diabetes mellitus (T2DM) patients with target organ damage. However, the evidence is insufficient to stratify the patients who will benefit from the intensive therapy among them. High visit-to-visit variability in systolic blood pressure (SBP) is associated with increased risk of cardiovascular events. We investigated the effectiveness of intensive versus standard statin therapy in the primary prevention of cardiovascular events among T2DM patients with retinopathy stratified by visit-to-visit SBP variability. METHODS The standard versus intensive statin therapy for hypercholesterolemic patients with diabetic retinopathy study was the first trial comparing statin intensive therapy targeting low-density lipoprotein cholesterol (LDL-C)

Aim Clinical evidence on cardiovascular health metrics of couples, as defined by the American Heart Association (AHA), remains to be scarce. This study aims to explore the correlation of the AHA-defined cardiovascular health metrics within couples using a nationwide epidemiological database. Methods We examined the modified cardiovascular health metrics among 87,160 heterosexual couples using the health claims database from the Japan Medical Data Center. The ideal cardiovascular health metrics is comprised of (1) nonsmoking, (2) body mass index ＜25 kg/m2, (3) physical activity at goal, (4) untreated blood pressure ＜120/80 mm Hg, (5) untreated fasting glucose ＜100 mg/dL, and (6) untreated total cholesterol ＜200 mg/dL. Results A correlation was noted on the ideal modified cardiovascular health metrics between couples. The prevalence of meeting ≥ 5 ideal components in the female partners increased from 32 % in the male partners meeting 0-1 ideal component to 56 % in those meeting 6 ideal components. The same trend has been observed in all generations (20-39 years, 40-49 years, 50-59 years, ≥ 60 years). The association between couples is found to be better in terms of smoking status, blood pressure, and fasting glucose level. Conclusion There was an intracouple correlation of the ideal modified cardiovascular health metrics, suggesting the importance of couple-based intervention to improve cardiovascular health status.