Evaluating convolutional neural network-enhanced electrocardiography for hypertrophic cardiomyopathy detection in a specialized cardiovascular setting.

The efficacy of convolutional neural network (CNN)-enhanced electrocardiography (ECG) in detecting hypertrophic cardiomyopathy (HCM) and dilated HCM (dHCM) remains uncertain in real-world applications. This retrospective study analyzed data from 19,170 patients (including 140 HCM or dHCM) in the Shinken Database (2010-2017). We evaluated the sensitivity, positive predictive rate (PPR), and F1 score of CNN-enhanced ECG in a ''basic diagnosis'' model (total disease label) and a ''comprehensive diagnosis'' model (including disease subtypes). Using all-lead ECG in the "basic diagnosis" model, we observed a sensitivity of 76%, PPR of 2.9%, and F1 score of 0.056. These metrics improved in cases with a diagnostic probability of ≥ 0.9 and left ventricular hypertrophy (LVH) on ECG: 100% sensitivity, 8.6% PPR, and 0.158 F1 score. The ''comprehensive diagnosis'' model further enhanced these figures to 100%, 13.0%, and 0.230, respectively. Performance was broadly consistent across CNN models using different lead configurations, particularly when including leads viewing the lateral walls. While the precision of CNN models in detecting HCM or dHCM in real-world settings is initially low, it improves by targeting specific patient groups and integrating disease subtype models. The use of ECGs with fewer leads, especially those involving the lateral walls, appears comparably effective.

Osteoclasts adapt to physioxia perturbation through DNA demethylation.

Oxygen plays an important role in diverse biological processes. However, since quantitation of the partial pressure of cellular oxygen in vivo is challenging, the extent of oxygen perturbation in situ and its cellular response remains underexplored. Using two-photon phosphorescence lifetime imaging microscopy, we determine the physiological range of oxygen tension in osteoclasts of live mice. We find that oxygen tension ranges from 17.4 to 36.4 mmHg, under hypoxic and normoxic conditions, respectively. Physiological normoxia thus corresponds to 5% and hypoxia to 2% oxygen in osteoclasts. Hypoxia in this range severely limits osteoclastogenesis, independent of energy metabolism and hypoxia-inducible factor activity. We observe that hypoxia decreases ten-eleven translocation (TET) activity. Tet2/3 cooperatively induces Prdm1 expression via oxygen-dependent DNA demethylation, which in turn activates NFATc1 required for osteoclastogenesis. Taken together, our results reveal that TET enzymes, acting as functional oxygen sensors, regulate osteoclastogenesis within the physiological range of oxygen tension, thus opening new avenues for research on in vivo response to oxygen perturbation.

Association between serum alkaline phosphatase and cardiovascular events in patients with atrial fibrillation.

High alkaline phosphatase (ALP) levels are reported to be associated with an increased risk of cardiovascular events in patients with chronic kidney disease (CKD). Given the pathological link with CKD, a similar relationship may exist in patients with atrial fibrillation (AF). We retrospectively evaluated 1,719 patients with AF and normal hepatic function who were registered in the Shinken Database between November 2011 and March 2017. Study patients were divided into three groups according to ALP value tertiles with cut-offs of 175 and 227 IU/L (normal range: 95-350 IU/L). Each group's incidence rate was recorded, and the risks of cardiovascular events and each component for patients in the middle and high ALP tertiles were compared with those in the low tertile and evaluated using Cox regression models. The additional predictive value of the high ALP tertile over the existing risk scores for the components of cardiovascular events was evaluated via receiver operating characteristic (ROC) curve analysis. During the median follow-up of 731 days (IQR: 444-1095 days), 137 cardiovascular events occurred, with incidence rates of 2.94%, 3.44%, and 6.19%/person-year for the low, middle, and high ALP tertiles, respectively. Of these cardiovascular events, heart failure had the highest incidence rates (1.34%, 1.89%, and 4.29%/person-year for the low, middle, and high ALP tertiles, respectively) and the incidence rates of the other components of cardiovascular event were similar in each ALP groups. Multivariate Cox regression analysis yielded hazard ratios of 1.22 (95% confidence interval [CI] 0.70-1.96) and 1.62 (95% CI 1.06-2.48) for cardiovascular events and 1.66 (95% CI 0.87-3.15) and 2.50 (95% CI 1.39-4.48) for heart failure admission in the middle and high ALP tertiles, respectively. By ROC curve analysis for heart failure admission showed that the high ALP tertile lacked significant additive predictive value over the existing risk scores. High serum ALP levels, even those in the normal range, were significantly associated with an increased risk of cardiovascular events, especially heart failure admission in patients with AF.

Glasgow prognostic score can be a prognostic indicator after percutaneous coronary intervention: a two-center study in Japan.

Glasgow prognostic score (GPS) has been used to evaluate inflammatory response and nutritional status. This study aimed to investigate the impact of nutritional status on cardiac prognosis by using GPS in patients after undergoing percutaneous coronary intervention (PCI). We included 862 patients who underwent PCI for stable angina pectoris between 2015 and 2018. We used the original cutoff values, which were an albumin (Alb) level of 3.5 g/dl and a C-reactive protein (CRP) level of 0.3 mg/dl. We categorized them into the three groups: originally defined GPS (od-GPS) 0 (high Alb and low CRP), 1 (low Alb or high CRP), and 2 (low Alb and high CRP). Major adverse clinical events (MACEs) included all-cause death, nonfatal myocardial infarction, revascularization, and hospitalization for heart failure. The median follow-up period was 398.5 days. During the follow-up, MACEs occurred in 136 patients. Od-GPS 2 had higher prevalence rates in terms of chronic kidney disease (CKD; 31.7% [229/722] vs. 44.9% [53/118] vs. 63.6% [14/22], p < 0.001), hemodialysis (6.4% [46/722] vs. 14.4% [17/118] vs. 31.8% [7/22], p < 0.001), and heart failure cases (HF; 9.1% [66/722] vs. 14.4% [17/118] vs. 27.3% [6/22], p = 0.007), with higher creatinine (1.17 ± 1.37 mg/dl vs. 1.89 ± 2.60 mg/dl vs. 3.49 ± 4.01 mg/dl, p < 0.001) and brain natriuretic peptide levels (104.1 ± 304.6 pg/ml vs. 242.4 ± 565.9 pg/ml vs. 668.1 ± 872.2 pg/ml, p < 0.001) and lower low-density lipoprotein cholesterol (101.5 ± 32.9 mg/dl vs. 98.2 ± 28.8 mg/dl vs. 77.1 ± 24.3 mg/dl, p = 0.002) than od-GPS 0 and 1.Od-GPS 2 (HR 2.42; 95% CI 1.16-5.02; p = 0.018), od-GPS 1 (HR 2.09; 95% CI 1.40-3.13; p < 0.001), diabetes (HR 1.41; 95% CI 1.00-1.99; p = 0.048), CKD (HR 2.10; 95% CI 1.49-2.96; p < 0.001), and HF (HR 1.64; 95% CI 1.05-2.56; p = 0.029) were independent predictors of MACEs. A scoring system using CRP and Alb levels with a milder definition than GPS suitably predicted the risk of MACEs in the patients who underwent PCI.

Relationship between resting 12-lead electrocardiogram and all-cause death in patients without structural heart disease: Shinken Database analysis.

BACKGROUND: Resting 12-lead electrocardiography is widely used for the detection of cardiac diseases. Electrocardiogram readings have been reported to be affected by aging and, therefore, can predict patient mortality. METHODS: A total of 12,837 patients without structural heart disease who underwent electrocardiography at baseline were identified in the Shinken Database among those registered between 2010 and 2017 (n = 19,170). Using 438 electrocardiography parameters, predictive models for all-cause death and cardiovascular (CV) death were developed by a support vector machine (SVM) algorithm. RESULTS: During the observation period of 320.4 days, 55 all-cause deaths and 23 CV deaths were observed. In the SVM prediction model, the mean c-statistics of 10 cross-validation models with training and testing datasets were 0.881 ± 0.027 and 0.927 ± 0.101, respectively, for all-cause death and 0.862 ± 0.029 and 0.897 ± 0.069, respectively for CV death. For both all-cause and CV death, high values of permutation importance in the ECG parameters were concentrated in the QRS complex and ST-T segment. CONCLUSIONS: Parameters acquired from 12-lead resting electrocardiography could be applied to predict the all-cause and CV deaths of patients without structural heart disease. The ECG parameters that greatly contributed to the prediction were concentrated in the QRS complex and ST-T segment.

Left atrial dimension and ischemic stroke in patients with and without atrial fibrillation.

The incidence of ischemic stroke (IS) increases in patients with enlarged left atrium (LA) irrespective of whether or not the existence of atrial fibrillation (AF). In such situation, it is unclear whether the impact of LA on incidence of IS still significant in young, non-AF patients with enlarged LA who are primarily unconcerned on anticoagulation therapy. The study population consisted of 18,511 consecutive patients not receiving oral anticoagulants and undergoing echocardiography with measurement of LAD at baseline. The incidence rate of ischemic stroke was calculated in 3 groups according to left atrial dimension (LAD; < 30, 30-45 and ≥ 45 mm) in AF and non-AF patients. Further subgroup analysis was performed in stratification by elderly and young (aged ≥ 65 and < 65 years, respectively). The incidences of IS (per 100 patient-years) were 0.11 and 0.71 in non-AF and AF patients with LAD < 30 mm, respectively, which increased to 0.58 and 1.35 in LAD ≥ 45 mm (adjusted hazard ratios [HRs]; 1.95 [95% confidence intervals, CIs: 0.76-5.01] and 1.22 [95% CIs: 0.27-5.58], interaction P was 0.246). In non-AF patients, the incidences of IS were 0.30 and 0.04 in elderly and young patients with LAD < 30 mm, which increased to 0.67 and 0.48 in LAD ≥ 45 mm (adjusted HRs; 1.34 [95% CIs: 0.43-4.15] and 4.21 [95% CIs: 0.77-23.12], interaction P was 0.158). The incidence of IS significantly increased with increase of LAD in non-AF, especially in non-AF and young patients, although the difference was not independent of other clinical factors. The impact of LAD on IS was numerically larger in non-AF than in AF, and larger in young and non-AF than in elderly counterpart, although a significant interaction was not observed in this small population. Further studies with large population are necessary to judge whether these population with enlarged LA need antithrombotic therapy.

Establishment of Novel Protein Interaction Assays between Sin3 and REST Using Surface Plasmon Resonance and Time-Resolved Fluorescence Energy Transfer.

Repressor element-1 (RE-1) or neural restrictive silencer element (NRSE) bound with a zinc finger transcription repressor, RE-1 silencing transcription factor (REST, also known as neural restrictive silencer factor, NRSF) has been identified as a fundamental repressor element in many genes, including neuronal genes. Genes regulated by REST/NRSF regulate multifaceted neuronal phenotypes, and their defects in the machinery cause neuropathies, disorders of neuron activity), autism and so on. In REST repressions, the N-terminal repressor domain recruits Sin3B via its paired amphipathic helix 1 (PAH1) domain, which plays an important role as a scaffold for histone deacetylase 1 and 2. This machinery has a critical role in maintaining neuronal robustness. In this study, in order to establish protein-protein interaction assays mimicking a binding surface between Sin3B and REST, we selected important amino acids from structural information of the PAH1/REST complex and then tried to reconstitute it using recombinant short peptides derived from PAH1/REST. Initially, we validated whether biotinylated REST interacts with glutathione S-transferase (GST)-tagged PAH1 and whether another PAH1 peptide (PAH1-FLAG) competitively binds with biotinylated REST using surface plasmon resonance (SPR). We observed a direct interaction and competitive binding of two PAH1 peptides. Secondly, in order to establish a high-throughput and high-dynamic-range assay, we utilized an easily performed novel time-resolved fluorescence energy transfer (TR-FRET) assay, and closely monitored this interaction. Finally, we succeeded in establishing a novel high-quality TR-FRET assay and a novel interaction assay based on SPR.

Seasonal Variations in the Incidence of Ischemic Stroke, Extracranial and Intracranial Hemorrhage in Atrial Fibrillation Patients.

BACKGROUND: Ischemic stroke (IS) and major bleeding, which are serious adverse events in patients with atrial fibrillation (AF), could have seasonal variations, but there are few reports.Methods and Results:In the Shinken Database 2004-2016 (n=22,018), 3,581 AF patients (average age, 63.5 years; 2,656 men, 74.2%; 1,388 persistent AF, 38.8%) were identified. Median CHADS2and HAS-BLED scores were both 1 point. Oral anticoagulants were prescribed for 2,082 (58.1%) patients (warfarin, 1,214; direct oral anticoagulants [DOACs], 868). Incidence and observation period (maximum 3 years) of IS, extracranial hemorrhage (ECH), and intracranial hemorrhage (ICH) were counted separately for the northern hemisphere seasons. During the mean follow-up period of 2.4 years, there were totals of 90 IS, 73 ECH, and 33 ICH cases. The respective incidence rates per 1,000 patient-years in spring, summer, autumn, and winter were 8.5, 8.8, 7.5, and 16.8 for IS, 7.2, 9.7, 3.8, and 13.1 for ECH, and 2.7, 1.9, 3.8, and 7.0 for ICH. The number of patients with DOACs relatively increased among those with ECH in summer. CONCLUSIONS: Significant seasonal variations were observed for IS, ECH, and ICH events in AF patients, and were consistently the highest in winter. A small peak of ECH was observed in summer, which seemed, in part, to be related to increased DOAC use.

Role of dipstick proteinuria for predicting cardiovascular events: a Japanese cardiovascular hospital database analysis.

Initial screening for proteinuria by urine dipstick test (UDT) may be useful for predicting clinical outcomes. The Shinken Database includes all the new patients visiting the Cardiovascular Institute Hospital in Tokyo, Japan. Patients for whom UDT was performed at their initial visit between 2004 and 2010 (n = 7131) were divided into three groups according to the test results: negative, trace, and positive (1+ to 4+) proteinuria. During the mean follow-up period of 3.4 years, 233 (3.1%) deaths, 255 (3.6%) heart failure (HF) events, and 106 (1.5%) ischemic stroke (IS) events occurred. Prevalence of atherothrombotic risks increased with an increase in the amounts of proteinuria. The incidence of all-cause death, HF and IS events increased significantly from negative to trace to positive proteinuria groups (log rank test, P for trend < 0.001). Multivariate analysis revealed independent association between proteinuria and all-cause death [hazard ratio (HR): 1.50, 95% confidence interval (CI) 1.07-2.10], HF (HR: 1.55, 95% CI 1.14-2.12), and IS (HR: 2.08, 95% CI 1.26-3.45). Even trace proteinuria was independently associated with HF (HR: 1.64, 95% CI 1.07-2.53) and IS (HR: 2.17, 95% CI 1.14-4.11) and with all-cause death (HR: 1.56, 95% CI 0.99-2.47). In conclusions, dipstick proteinuria was independently associated with cardiovascular events and death, suggesting that the UDT is a useful tool for evaluating patients' risk for such adverse events.

Creatinine clearance and inappropriate dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation.

In Japanese surveillance in an early phase after the approval of rivaroxaban, inappropriate underdose was frequently utilized. The aim of this study was to describe the prevalence and predictors of the inappropriate usage of rivaroxaban in a single-center, cardiovascular-specialized hospital. Consecutive 661 non-valvular atrial fibrillation (NVAF) patients treated with rivaroxaban between 2012 and 2017 were recruited. After excluding 30 patients without assessment of creatinine clearance (CCr), the proportion and predictors of inappropriate underdose were analyzed. Additionally, patient outcomes, including thromboembolism (ischemic stroke or systemic embolism) and major bleeding, were determined. In patients with CCr ≥ 50 mL/min (n = 532) and < 50 mL/min (n = 98), inappropriate underdose and overdose were used in 123 (23%) and 8 (8%), respectively. The predictors of inappropriate underdose (in patients with CCr ≥ 50 mL/min) were CCr [50-63 mL/min (the lowest tertile) compared to ≥ 64 mL/min], age ( ≥ 75 years), female gender, prescription of antiplatelet, and coexistence of heart failure. Although PT under rivaroxaban was lower in patients with inappropriate underdose than in those with an appropriate dose, no significant increase in the incidence of thromboembolism or major bleeding was observed within the mean follow-up of 683 days. Inappropriate underdose of rivaroxaban was frequently observed for NVAF patents even in a cardiovascular hospital, particularly in patients with CCr adjacent to the dose reduction criteria. The responses of PT and the incidence of adverse outcomes under an inappropriate dose of rivaroxaban should be further investigated.

Myocardial bridging is an independent predictor of positive spasm provocation testing by intracoronary ergonovine injections: a retrospective observational study.

The relationship between myocardial bridging (MB) and coronary spasms during spasm provocation testing (SPT) remains unclear. We aimed to investigate whether MB was correlated with the SPT by ergonovine (ER) injections in a retrospective observational study. Of the 3340 patients who underwent a first coronary angiography, 166 underwent SPT using ER injections and were divided into 2 groups: MB(+) (n = 23), and MB(-) (n = 143). MB was defined as an angiographic reduction in the diameter of the coronary artery during systole. The patients who had severe organic stenosis in the left anterior descending coronary artery were excluded. The MB(+) group more frequently had diabetes mellitus and chronic kidney disease, and a thicker interventricular septum thickness. The rate of SPT-positivity was higher in the MB(+) group than MB(-) group (56.5% vs. 22.4%, P = 0.001). A multivariate regression analysis showed that the presence of MB was independently associated with SPT-positivity (odds ratio 5.587, 95% confidence interval 2.061-15.149, P = 0.001). In conclusion, coronary spasms during provocation tests with ER independently correlated with the MB. MB may predict coronary spasms.

Differences in treatment and prognosis by the experience of falls or bone fracture in elderly patients with atrial fibrillation.

Treatment and prognosis of elderly patients with atrial fibrillation (AF) may differ by the experience of fall or bone fracture. However, their current status is still unclear. From our institute database between 2010 and 2015, 674 AF patients with age ≥ 70 years were selected and were divided into those who experienced fall or fracture during the observation period (F/F group; n = 49) and those who did not (non-F/F group; n = 625). We compared the treatment and prognosis between the 2 groups. Patients in the F/F group were older (79 vs 76 years, P < 0.001) and had more comorbidities compared with those in the non-F/F group. The prescription rate of oral anticoagulant was similar between the two groups (77.6% vs 68.2%, P = 0.201), where warfarin was predominant. The F/F group was not associated with higher incidence of ischemic stroke. The F/F group was associated with a higher incidence of heart failure events (adjusted odds ratio (OR) 3.88; 95% confidence intervals (Cl) 1.70-8.85; P = 0.001), and cardiovascular events (OR 3.43; 95% Cl 1.71-6.85; P < 0.001). In elderly AF patients in a cardiovascular hospital, the experience of fall or fracture did not affect the prescription of oral anticoagulants and the incidence of ischemic stroke, but it was significantly associated with increase of heart failure.

Establishment of Novel High-Standard Chemiluminescent Assay for NTPase in Two Protozoans and Its High-Throughput Screening.

Toxoplasma gondii is a major protozoan parasite and infects human and many other warm-blooded animals. The infection leads to Toxoplasmosis, a serious issue in AIDS patients, organ transplant recipients and pregnant women. Neospora caninum, another type of protozoa, is closely related to Toxoplasma gondii. Infections of the protozoa in animals also causes serious diseases such as Encephalomyelitis and Myositis-Polyradiculitis in dogs or abortion in cows. Both Toxoplasma gondii and Neospora caninum have similar nucleoside triphosphate hydrolases (NTPase), NcNTPase and TgNTPase-I in Neospora caninum and Toxoplasma gondii, respectively. These possibly play important roles in propagation and survival. Thus, we targeted the enzymes for drug discovery and tried to establish a novel high-standard assay by a combination of original biochemical enzyme assay and fluorescent assay to determine ADP content. We then validated whether or not it can be applied to high-throughput screening (HTS). Then, it fulfilled criterion to carry out HTS in both of the enzymes. In order to identify small molecules having inhibitory effects on the protozoan enzyme, we also performed HTS using two synthetic compound libraries and an extract library derived from marine bacteria and then, identified 19 compounds and 6 extracts. Nagasaki University collected many extracts from over 18,000 marine bacteria found in local Omura bay, and continues to compile an extensive collection of synthetic compounds from numerous drug libraries established by Japanese chemists.

Novel Reporter System Monitoring IL-18 Specific Signaling Can Be Applied to High-Throughput Screening.

Very recently, the immunotherapies against cancer, autoimmune diseases, and infection have been feasible and promising. Thus, we have examined the possibility whether or not human gamma delta T cells can be applied for the novel immunotherapies. We previously established the cells stably maintaining NFkB-driven human secreted embryonic alkaline phosphatase (SEAP) expression. The cells can be used to determine the transcription activity of NFkB with high-standard dynamic range and accuracy. Because IL-18 is a kind of cytokines that enhances cytotoxicity and activity of human gamma delta T cells through NFkB activation, we have focused on the activity and signaling of IL-18. In this study, we modified the previous reporter cell that can determine the transcription activity of NFkB to express two subunits consisted of human IL-18 receptor. The modified cells secreted SEAP in response to treatment with human recombinant IL-18 in a concentration-dependent manner. We also observed the concentration-dependently enhancement of NFkB activity in the cells treated with mouse recombinant IL-18 although the affinity was lower compared to human recombinant IL-18. We also previously established the cells stably expressing and secreting human recombinant IL-18 and then validated whether or not the conditioned medium from the cells activate NFkB transcription activity using this assay. Our university has kept collecting many extracts from over 18,000 marine bacteria in our local sea around Omura bay-fungi, plants for Chinese herbal medicine, and so on-and also have kept gathering synthetic compounds from many Japanese chemists as drug libraries. Finally, in order to identify drugs mimicking IL-18 biological activity or possessing inhibitory effects on IL-18-induced NFkB, we demonstrated drug screening using number of extracts derived from marine bacteria and synthetic compounds.

Association Between Dose and Plasma Concentration of Bisoprolol in Patients with Heart Failure (CVI ARO 6).

Although bisoprolol is used widely to treat patients with heart failure (HF), little information is available regarding the association between the dose of bisoprolol administered and the bisoprolol plasma concentration (Bis-PC) in real-world clinical practice.This was a single-center, observational study in 114 patients with HF receiving once-daily bisoprolol. After determination of trough Bis-PC, the relationship between the dose of bisoprolol and Bis-PC was analyzed. In a multiple linear regression model, the dose of bisoprolol and estimated creatinine clearance (reciprocal number) were identified as independent predictors. HF severity and hepatic function were not associated with Bis-PC.Bis-PC was increased by renal dysfunction, which explained most of the discrepancy between the dose of bisoprolol administered and Bis-PC.

Eleven-year temporal trends of clinical characteristics and long-term outcomes in patients undergoing percutaneous coronary intervention for acute coronary syndrome in the Shinken database.

Despite the increasing incidence of acute coronary syndrome (ACS) in Japan, its prognosis has improved. However, there is a paucity of longitudinal registry data providing trends of in-hospital care and prognosis of ACS in Japan. ACS patients undergoing percutaneous coronary intervention (PCI) included in the Shinken Database 2004-2014 were divided into two groups according to admission year (2004-2009, n = 390; 2010-2014, n = 328). Patient characteristics, lesion/procedure characteristics, medications at discharge, all-cause mortality, cardiovascular death, acute myocardial infarction (AMI), target lesion revascularization (TLR), re-PCI to new lesion, and coronary artery bypass graft (CABG) within 2 years after discharge were compared between the groups. Prevalence of hypertension, dyslipidemia, and dual antiplatelet/statin prescription increased significantly between periods. Usage of second-generation drug-eluting stents (DES) increased markedly between the two periods (2.6, 66.8%), while those of bare metal stents (64.4, 26.5%) and first-generation DES (25.6, 1.5%) decreased (all, p < 0.01). Two-year event-free survival rate increased for all-cause mortality (94.6-98.3%, p = 0.01), TLR (79.4-96.1%, p < 0.01), and re-PCI to new lesion (87.3-95.1%, p < 0.01). There were no significant differences in cardiovascular death, AMI, or CABG between the two periods. The event-free rates for TLR and re-PCI to new lesion in ACS patients have increased over the last decade in Japan. These observations should be confirmed in larger, longitudinal, multicenter registries.

Predictors of International Normalized Ratio Variability in Patients With Atrial Fibrillation Under Warfarin Therapy.

BACKGROUND: Variability in the international normalized ratio (INR) of prothrombin time has been suggested to be related to outcome in patients with atrial fibrillation (AF) under warfarin therapy, but its determinants remain unclear.Methods and Results:The study population consisted of 626 AF patients under warfarin therapy in the Shinken Database (n=22,230). INR variability was calculated by Fihn's method. Determinants of high log INR variability (defined as over mean+standard deviation) were determined by logistic regression analyses. Symptomatic heart failure (odds ratio [OR] 3.974, 95% confidence interval [CI] 2.510-6.292), older age (≥75 years old; OR 2.984, 95% CI 1.844-4.826) and severe renal dysfunction (eGFR <30 mL/min/1.73 m2; OR 3.918, 95% CI 1.742-8.813) were identified as independent predictors of high INR variability on multivariate logistic regression analysis. CONCLUSIONS: The determinants of INR variability in AF patients under warfarin therapy could assist Japanese clinicians in identifying patients likely to show unstable warfarin control irrespective of the definition of the target INR range.

Impact of BNP level and peak VO2 on future heart failure events: comparison between sinus rhythm and atrial fibrillation.

This study aimed to examine the discrete impacts of peak oxygen consumption (VO2) and brain natriuretic peptide (BNP) levels on future heart failure (HF) events in sinus rhythm (SR) and atrial fibrillation (AF). A total of 1447 patients who underwent symptom-limited cardiopulmonary exercise testing and whose BNP values were determined simultaneously were analysed (SR, N = 1151 and AF, N = 296). HF events were defined as HF hospitalization or HF death. Over a mean follow-up period of 1472 days, 140 HF events were observed. A high BNP value (dichotomized by median value) was independently associated with HF events in SR (HR 8.08; 95 % CI 4.02-16.26; p < 0.0001), but not in AF patients (HR 1.97; 95 % CI 0.91-4.28; p = 0.087) with a significant interaction between the rhythms. By contrast, low-peak VO2 was independently associated with HF events in both rhythms (AF; HR 5.81; 95 % CI 1.75-19.30; p = 0.004, SR; HR 2.04; 95 % CI 1.19-3.49; p = 0.009), with a marginal interaction between them. In bivariate Cox models, low-peak VO2 had much stronger predictive power for HF events than high-BNP in AF, whereas high-BNP was more powerful than low-peak VO2 in SR. The prognostic value of BNP and peak VO2 for future HF events seemed to be different between SR and AF.

Effects of Smoking on Ischemic Stroke, Intracranial Hemorrhage, and Coronary Artery Events in Japanese Patients With Non-Valvular Atrial Fibrillation.

The effects of smoking on the prognosis of non-valvular atrial fibrillation (NVAF) patients are unclear.The Shinken Database 2004-11 (n = 17,517) includes all new patients visiting the Cardiovascular Institute between June 2004 and March 2012. Among these cases, 2,102 NVAF patients were identified. The effects of smoking on ischemic stroke (IS), intracranial hemorrhage (ICH), and coronary artery events including percutaneous coronary intervention (PCI) and acute coronary syndrome (ACS) were analyzed. Smokers were younger and had lower risk profiles compared with non-smokers. A similar tendency was observed between current and former smokers. In contrast, patients with high tobacco consumption were older and had higher risk profiles, including uncontrolled hypertension, compared with those with low tobacco consumption. In 8,159 patient-years, IS, ICH, PCI, and ACS occurred at rates of 7.7, 2.7, 12.4, and 3.0 per 1000 patient-years. In multivariate Cox regression analysis, smoking was not significantly associated with any adverse event. However, different effects of smoking were observed when stratified by age. In patients ≥ 65 years old, current smokers were independently associated with PCI. Moreover, current smokers and smokers with a total tobacco amount ≥ 800 were marginally and independently associated with IS. In patients < 65 years, current smokers were independently associated with ICH.Age appears to be one of the contributors to differentiation of the effects of smoking on cardiovascular events in our NVAF patients. In elderly patients who still smoke, smoking was associated with the promotion of atherosclerosis or thromboembolism, whereas in young patients it was associated with bleeding.

Nine-Year Trend of Anticoagulation Use, Thromboembolic Events, and Major Bleeding in Patients With Non-Valvular Atrial Fibrillation　- Shinken Database Analysis.

BACKGROUND: Trends of oral anticoagulant (OAC) prescription and incidence of thromboembolism (TE) and/or major bleeding (MB) in patients with non-valvular atrial fibrillation (NVAF) in Japan are still unclear. METHODS AND RESULTS: We used data from Shinken Database 2004-2012, which included all new patients attending the Cardiovascular Institute between June 2004 and March 2013. Of them, 2,434 patients were diagnosed with NVAF. Patients were divided into 3 time periods according to the year of initial visit: 2004-2006 (n=681), 2007-2009 (n=833), and 2010-2012 (n=920). OAC prescription rate steadily increased from 2004-2006 to 2010-2012. Between 2004-2006 and 2007-2009, irrespective of increased warfarin usage, MB tended to decrease, presumably due to low-intensity therapy and avoidance of concomitant use of dual antiplatelets, but TE did not improve. In 2010-2012, direct OACs (DOAC), preferred in low-risk patients, may have contributed to not only decrease TE, but also increase MB, especially extracranial bleeds. In high-risk patients in that time period, mostly treated with warfarin, incidence of TE and MB did not improve. CONCLUSIONS: The 9-year trend of stroke prevention indicated a steady increase of OAC prescription and a partial improvement of TE and MB. Even in the era of DOAC, TE prevention was insufficient in high-risk patients, and DOAC were associated with increased extracranial bleeding. (Circ J 2016; 80: 639-649).