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Background: The development of numerous disease-modifying drugs for age-related dementia has been attempted based on the amyloid-β (Aβ) hypothesis without much success. Taxifolin (TAX), a natural bioactive flavonoid, shows pleiotropic neuroprotective effects with inhibition of Aβ aggregation, production, and glycation, antiinflammatory effects, and amelioration of the waste clearance system. We hypothesized that TAX intake is associated with the suppression of cognitive deterioration. Objective: To investigate associations between TAX intake and cognitive changes. Methods: We retrospectively identified patients who orally took TAX 300 mg/day and regularly underwent Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog) and Montreal Cognitive Assessment (MoCA) and compared the temporal changes in ADAS-Cog and MoCA between the non-treatment (pre-TAX) period (180±100 days) and following treatment (on-TAX) period (180±100 days) from June 2020 to November 2021. Since some additional patients underwent the Mini-Mental State Examination (MMSE) instead of the MoCA at the beginning of the pre-TAX period, the same comparison was performed using the MoCA total score converted from MMSE as a sensitivity analysis. Results: Sixteen patients were identified. TAX intake was associated with significantly higher interval changes in the MoCA subscale scores of visuospatial/executive function (p = 0.016), verbal fluency (p = 0.02), and the total score (p = 0.034), but not with ADAS-Cog (total score, p = 0.27). In the sensitivity analysis, 29 patients were included. TAX intake was associated with a significantly higher interval change in the total MoCA score (p = 0.004) but not with ADAS-Cog (p = 0.41). Conclusion: Our findings provide a basis for TAX as a novel strategy for maintaining brain health during aging. A prospective cohort study is required to confirm these findings.

Indwelling urethral catheters (IUCs) are used to measure urine volume, keep patients on bed rest, or keep the groin area clean in patients with acute myocardial infarction (AMI). However, the association between IUC use and in-hospital urinary-related complications is unknown.This was a single-center retrospective analysis of 303 patients admitted to our hospital in 2018-2020 who had AMI without cardiogenic shock. An IUC was inserted in the emergency room upon initiation of invasive catheter treatment and removed as soon as possible. The primary outcome was in-hospital adverse urinary event (IHAUE), which consisted of in-hospital urinary tract infection and in-hospital gross hematuria.Of 303 patients, 243 patients (80.2 %) underwent IUC insertion. A lower proportion of patients with IUCs were male (72 % vs. 85 %, p = 0.044). A higher proportion had Killip classification 2 or 3 (13 % vs. 0 %, p = 0.003) or ST-elevation myocardial infarction (65 % vs. 32 %, p 0.001). IHAUEs occurred significantly more commonly in patients with IUCs than without IUCs (11 % vs. 2 %, p = 0.023). Kaplan-Meier analysis showed that IHAUEs occurred more frequently in patients with IUCs than patients without IUCs (log-rank test p = 0.033). Furthermore, IUC use longer than the median of 2 days was associated with a higher odds ratio (OR) for IHAUE when compared with those without IUC use (OR, 3.65; 95 % confidence interval, 1.28-10.4; p = 0.015). There were no significant differences in in-hospital mortality by IUC status.IUC use is associated with a higher risk of IHAUEs in patients with uncomplicated AMI. Routine IUC use might not be recommended.

Background Mechanism of femoropopliteal in-stent restenosis has been underappreciated. Aim The aim of this animal study was to elucidate vascular response after femoropopliteal bare nitinol self-expanding stents (SESs) implantation. Methods Misago, Smart Flex, or Innova stent was randomly implanted in 36 swine femoropopliteal arteries. At week 4, quantitative vessel analysis (QVA) was performed on 36 legs, of which 18 underwent histological evaluation after angiography. The remaining 18 legs underwent QVA and histological evaluation at week 13. Results Fibrin deposition was excessive at week 4. Internal elastic lamina (IEL) progressively enlarged over time, and vessel injury developed from mild level at week 4 to moderate level at week 13. Vessel inflammatory reaction was mild to moderate at week 4, and was moderate to severe at week 13. Increased fibrin deposition was an early-acting, IEL enlargement and increased vessel inflammation were long-acting, and increased vessel injury and giant cells infiltration were late-acting contributors to neointimal hyperplasia (NIH). Stent type altered time-dependent process of vessel injury, vessel inflammation, eosinophils and giant cells infiltration. Misago had less fibrin deposition and vessel enlargement, and less progressive vessel injury, vessel inflammation, and eosinophils and giant cells infiltration. Net lumen as assessed by percent diameter stenosis or minimum lumen diameter was preserved with Misago, but was not preserved with the other stents. Conclusions In the context of bare nitinol SES platform with less progressive mechanical stress and inflammatory reaction, the advantage of less NIH outweighed the disadvantage of less vessel enlargement, leading to net lumen preservation.

To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case-control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE.We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models.The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT-S and 0.88 [p = 0.001] for CAVE-S at the testing data).Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2022.

Aims Detection of asymptomatic paroxysmal atrial fibrillation is challenging. Smartphone- or smartwatch-based photoplethysmography is efficient at detecting irregular rhythms using pulse waves but is too complex for older patients. We aimed to evaluate the detection accuracy of atrial fibrillation by a wristwatch-type continuous pulse wave monitor (PWM) in daily life. Methods and results Patients at high risk of atrial fibrillation but with no history of atrial fibrillation (n = 163; mean CHADS2 score, 1.9) and patients with known atrial fibrillation (n = 123, including 34 with persistent atrial fibrillation) underwent PWM and telemetry electrocardiogram recording for 3 days. Risk of atrial fibrillation was judged using the ‘Kyorin Atrial Fibrillation Risk Score’, a scoring system based on previously reported atrial fibrillation risk scoring systems. The PWM assessed the presence of atrial fibrillation at 30 min intervals, and the results were compared with the telemetry electrocardiogram findings. The PWMs accurately diagnosed two patients with paroxysmal atrial fibrillation in the high-risk group. The PWMs accurately diagnosed 48 of the 55 patients with atrial fibrillation in the known-atrial fibrillation group. The PWM accuracy in detecting patients with atrial fibrillation was as follows: sensitivity, 98.0%; specificity, 90.6%; positive predictive value, 69.4%; negative predictive value, 99.5%. The respective values for intervals with atrial fibrillation were 86.9%, 98.8%, 89.6%, and 98.5%. Conclusion The wristwatch-type PWM has shown feasibility in detecting atrial fibrillation in daily life and showed the possibility of being used as a screening tool.

Background: ANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP. Methods and Results: Immunohistochemical analysis of rat tissues revealed that NPR1 was abundantly expressed in endothelial cells and smooth muscle cells of small arteries and arterioles. Intravenous infusion of ANP significantly lowered systolic blood pressure in wild-type mice. ANP also significantly lowered systolic blood pressure in smooth muscle cell–specific Npr1 –knockout mice but not in endothelial cell–specific Npr1 –knockout mice. Moreover, ANP significantly lowered systolic blood pressure in Nos3 -knockout mice. In human umbilical vein endothelial cells, treatment with ANP did not influence nitric oxide production or intracellular Ca 2+ concentration, but it did hyperpolarize the cells. ANP-induced hyperpolarization of human umbilical vein endothelial cells was inhibited by several potassium channel blockers and was also abolished under knockdown of RGS2 (regulator of G-protein signaling 2), an GTPase activating protein in G-protein α-subunit. ANP increased Rgs2 mRNA expression in human umbilical vein endothelial cells but failed to lower systolic blood pressure in Rgs2 -knockout mice. Endothelial cell–specific Npr1 -overexpressing mice exhibited lower blood pressure than did wild-type mice independent of RGS2, and showed dilation of arterial vessels on synchrotron radiation microangiography. Conclusions: Together, these results indicate that vascular endothelial NPR1 plays a crucial role in ANP-mediated blood pressure regulation, presumably by a mechanism that is RGS2-dependent in the acute phase and RGS2-independent in the chronic phase.

BackgroundDespite advances in pre- and post-resuscitation care, percentage of survival to hospital discharge after out-of-hospital cardiac arrest (OHCA) was extremely low. Development of an accurate system to predict the daily incidence of OHCA might provide a significant public health benefit. Here, we developed and validated a machine learning (ML) predictive model for daily OHCA incidence using high-resolution meteorological, chronological, and geographical data.MethodsWe analyzed a dataset from the United States that combined an OHCA nationwide registry, high-resolution meteorological data, chronological data, and geographical data. We developed a model to predict daily OHCA incidence with a training dataset for 2013–2017 using the eXtreme Gradient Boosting algorithm. A dataset for 2018–2019 was used to test the predictive model. The main outcome was the predictive accuracy for the number of daily OHCA events, based on root mean squared error (RMSE), mean absolute error (MAE), and mean absolute percentage error (MAPE). In general, a model with MAPE less than 10% is considered highly accurate.ResultsAmong the 446,830 OHCAs of non-traumatic cause where resuscitative efforts were initiated by a 911 responder, 264,916 in the training dataset and 181,914 in the testing dataset were included in the analysis. The ML model with combined meteorological, chronological, and geographical data had high predictive accuracy in relation to nationwide incidence rate per 100,000 at the nationwide level) in the training dataset (RMSE, 0.016; MAE, 0.013; and MAPE, 7.61%) and in the testing dataset (RMSE, 0.018; MAE, 0.014; and MAPE, 6.52%).ConclusionsA ML predictive model using comprehensive daily meteorological, chronological, and geographical data allows for highly precise estimates of OHCA incidence in the United States.Clinical PerspectiveWhat is new?A machine learning predictive model developed with a high-resolution meteorological dataset and chronological and geographical variables predicted the daily incidence of out-of-hospital cardiac arrest (OHCA) in the U.S. population with high precision. The predictive accuracy at the state level was greater in medium and high-temperature areas than in the low-temperature area.What are the clinical implications?This predictive model revealed complex associations between meteorological, chronological, and geographic variables in relation to predicting daily incidence of OHCA. It might be useful for public health strategies in temperate regions, for example, by providing a warning system for citizens and emergency medical services agencies on high-risk days.

Background: Intravascular imaging has shown better response of coronary atheroma to statin-mediated lowering of low-density lipoprotein cholesterol in women. However, its detailed mechanism remains to be determined yet. Modifiability of coronary atheroma under lipid-lowering therapies is partly driven by lipidic plaque component. Given a smaller plaque volume in women, lipidic plaque features including their density may differ between sex. Therefore, the current study sought to characterize sex-related differences in the density of lipidic plaque. Methods: We analyzed 1429 coronary lesions (culprit/nonculprit lesions=825/604) in 758 coronary artery disease patients (men/women=608/150) from the REASSURE-NIRS multicenter registry (Revelation of Pathophysiological Phenotypes of Vulnerable Lipid-Rich Plaque on Near-Infrared Spectroscopy). Total atheroma volume at 4-mm segment, maximum 4-mm-lipid-core burden index, and lipid plaque density index (=maximum 4-mm-lipid-core burden index/total atheroma volume at 4-mm segment) on near-infrared spectroscopy/intravascular ultrasound imaging at culprit and nonculprit lesions were compared in men and women. Results: Statin and high-intensity statin were used in 72.4 ( P =0.81) and 22.9% ( P =0.32) of study subjects, respectively. Women exhibited a smaller adjusted total atheroma volume at 4-mm segment (culprit lesions: 50.3±0.4 versus 54.2±0.3mm 3 , P 3 , P P =0.11, nonculprit lesions: 288.8±26.7 versus 272.7±18.9, P =0.51). Furthermore, a greater adjusted lipid plaque density index was observed in women (culprit lesions: 18.2±0.9 versus 9.8±0.6, P P Conclusions: Women harbored greater condensed lipidic plaque features, accompanied by smaller atheroma volume. These observations indicate potentially better modifiable disease in women, which underscores the need to intensify their lipid-lowering therapies for further improving their outcomes. Registration: URL: https://www.clinicaltrials.gov/ ; Unique identifier: NCT04864171

Background Differences in the clinical course of heritable thoracic aortic disease based on the disease‐causing gene have not been fully evaluated. To clarify the clinical relevance of causative genes in heritable thoracic aortic disease, we assessed the clinical course of patients categorized based on genetic diagnosis. Methods and Results We investigated cardiovascular events and mortality in 518 genetically diagnosed patients in 4 groups: Group 1, FBN1 (n=344); Group 2, TGFBR1 , TGFBR2 , SMAD3 , or TGFB2 (n=74); Group 3, COL3A1 (n=60); and Group 4, ACTA2 or MYH11 (n=40). The median age at the first cardiovascular event ranged from 30.0 to 35.5 years ( P =0.36). Patients with gene variants related to transforming growth factor‐β signaling had a significantly higher rate of subsequent events than those with FBN1 variants (adjusted hazard ratio, 2.33 [95% CI, 1.60–3.38]; P P =0.06). Female patients with COL3A1 variants had a significantly lower incidence than female patients in the other 3 groups (34.2%, 59.0%, 3.1%, and 43.8%, respectively; P Conclusions Gene variants related to transforming growth factor‐β signaling are associated with a higher incidence of subsequent cardiovascular events than FBN1 variants. COL3A1 variants might be related to a lower incidence of aortic dissection than other gene variants in women only. Identifying the genetic background of patients with heritable thoracic aortic disease is important for determining appropriate treatment.

Background and ObjectivesThe functional outcome and mortality of patients with poststroke epilepsy (PSE) have not been assessed in a prospective study. Previous reports have suggested that patients with PSE may suffer from prolonged functional deterioration after a seizure. In this study, we prospectively investigated the functional outcome and mortality of patients with PSE and analyzed the effect of seizure recurrence on the outcomes.MethodsThis is part of the Prognosis of Post-Stroke Epilepsy study, a multicenter, prospective observational cohort study, where 392 patients with PSE (at least 1 unprovoked seizure more than 7 days after the onset of the last symptomatic stroke) were followed for at least 1 year at 8 hospitals in Japan. This study included only PSE patients with a first-ever seizure and assessed their functional decline and mortality at 1 year. Functional decline was defined as an increase in modified Rankin Scale (mRS) score at 1 year compared with baseline, excluding death. The associations between the seizure recurrence and the outcomes were analyzed statistically.ResultsA total of 211 patients (median age of 75 years; median mRS score of 3) were identified. At 1 year, 50 patients (23.7%) experienced seizure recurrence. Regarding outcomes, 25 patients (11.8%) demonstrated functional decline and 20 (9.5%) had died. Most patients died of pneumonia or cardiac disease (7 patients each), and no known causes of death were directly related to recurrent seizures. Seizure recurrence was significantly associated with functional decline (odds ratio [OR] 2.96, 95% CI 1.25–7.03, p = 0.01), even after adjusting for potential confounders (adjusted OR 3.26, 95% CI 1.27–8.36, p = 0.01), but not with mortality (OR 0.79, 95% CI 0.25–2.48, p = 0.68). Moreover, there was a significant trend where patients with more recurrent seizures were more likely to have functional decline (8.7%, 20.6%, and 28.6% in none, 1, and 2 or more recurrent seizures, respectively; p = 0.006).DiscussionOne-year functional outcome and mortality of patients with PSE were poor. Seizure recurrence was significantly associated with functional outcome, but not with mortality. Further studies are needed to ascertain whether early and adequate antiseizure treatment can prevent the functional deterioration of patients with PSE.

Background The additional effects of single-antiplatelet therapy (SAPT) on anticoagulant therapy are still unclear in patients with atrial fibrillation (AF) after bioprosthetic valve replacement.Methods and Results:We conducted a subanalysis of a multicenter, retrospective, observational registry of patients with bioprosthetic valves and AF in Japan. Patients administered anticoagulants alone comprised the ACA group (n=107), and patients given concomitant SAPT and anticoagulant therapy comprised the On SAPT group (n=82). The primary efficacy endpoint was the incidence of stroke/systemic embolism, and the primary safety endpoint was the incidence of major bleeding. The observation period was 46.3±24.6 months. The primary efficacy endpoint occurred in 12 patients, and the cumulative incidence of primary efficacy events was significantly higher in the ACA group compared with the On SAPT group (P=0.039). The primary safety endpoint occurred in 22 patients, and the cumulative incidence of primary safety events was similar between groups (P=0.66). No differences between the groups were observed for cardiac events. Conclusions Additional SAPT on anticoagulant therapy in patients with bioprosthetic valves and AF was associated with a reduction in stroke/systemic embolic events, although the cumulative incidence of bleeding was similar, regardless of additional SAPT. These findings suggest that additional SAPT on anticoagulant therapy may be safe and effective in real-world clinical settings.

Postprocedural mitral stenosis (MS), or increased transmitral mean pressure gradient (TMPG), is one of the limitations of transcatheter edge-to-edge mitral valve repair using MitraClip (Abbott Vascular Inc., Santa Clara, USA); however, the usefulness of three-dimensional transesophageal echocardiography (3D-TEE) for predicting postprocedural MS in functional mitral regurgitation (MR) has not been fully elucidated.Eighty-two consecutive functional MR patients who underwent transcatheter mitral valve repair using MitraClip were retrospectively studied. Postprocedural MS was defined as TMPG ≥ 5 mmHg by echocardiography.Ten patients had postprocedural MS, and 3D-TEE showed that patients with postprocedural MS had smaller preprocedural mitral valve orifice area (MVOA), anteroposterior and mediolateral diameter, leaflet area, and annulus area. Receiver operating characteristic analysis showed that leaflet area (area under the curve (AUC) 0.829), annulus area (AUC 0.813), anteroposterior diameter (AUC 0.797) and mediolateral diameter (AUC 0.803) evaluated using 3D-TEE were predictors of postprocedural MS, and their predictive abilities were higher than those of preprocedural MVOA (AUC 0.756) and preprocedural TMPG (AUC 0.716). Adding leaflet area to TMPG and MVOA resulted in higher C-statistics for predicting postprocedural MS (from 0.716 to 0.845 and from 0.756 to 0.853, respectively).In functional MR patients treated with MitraClip, leaflet area and annulus area evaluated using 3D-TEE had high predictive values for postprocedural MS, and their predictive abilities were higher than those of preprocedural TMPG or MVOA.

Background Acute myocardial infarction (AMI) infrequently occurs after acute stroke. The Heart‐brain team approach has a potential to appropriately manage this poststroke cardiovascular complication. However, clinical outcomes of AMI complicating acute stroke (AMI‐CAS) with the heart‐brain team approach have not been characterized. The current study investigated cardiovascular outcomes in patients with AMI‐CAS managed by a heart‐brain team. Methods and Results We retrospectively analyzed 2390 patients with AMI at our institute (January 1, 2007–September 30, 2020). AMI‐CAS was defined as the occurrence of AMI within 14 days after acute stroke. Major adverse cerebral/cardiovascular events (cardiac‐cause death, nonfatal myocardial infarction, and nonfatal stroke) and major bleeding events were compared in subjects with AMI‐CAS and those without acute stroke. AMI‐CAS was identified in 1.6% of the subjects. Most AMI‐CASs (37/39=94.9%) presented ischemic stroke. Median duration of AMI from the onset of acute stroke was 2 days. Patients with AMI‐CAS less frequently received primary percutaneous coronary intervention (43.6% versus 84.7%; P P P P P =0.009). These relationships still existed even after adjusting for clinical characteristics and medication use (major adverse cerebral/cardiovascular event: HR, 1.87 [95% CI, 1.02–3.42]; P =0.04; major bleeding: HR, 2.67 [95% CI, 1.03–6.93]; P =0.04). Conclusions Under the heart‐brain team approach, AMI‐CAS was still a challenging disease, reflected by less adoption of primary percutaneous coronary intervention and antithrombotic therapies, with substantially elevated cardiovascular and major bleeding risks. Our findings underscore the need for a further refined approach to mitigate their ischemic/bleeding risks.

BACKGROUND The impact of chronic kidney disease (CKD) on long-term outcomes following acute myocardial infarction (AMI) in the era of modern primary PCI with optimal medical therapy is still in debate.Methods and Results:A total of 3,281 patients with AMI were enrolled in the J-MINUET registry, with primary PCI of 93.1% in STEMI. CKD stage on admission was classified into: no CKD (eGFR ≥60 mL/min/1.73 m2); moderate CKD (60>eGFR≥30 mL/min/1.73 m2); and severe CKD (eGFR

Background The high mortality of acute myocardial infarction (AMI) with cardiogenic shock (i.e., Killip class IV AMI) remains a challenge in emergency cardiovascular care. This study aimed to examine institutional factors, including the number of JCS board-certified members, that are independently associated with the prognosis of Killip class IV AMI patients.Methods and Results:In the Japanese registry of all cardiac and vascular diseases-diagnosis procedure combination (JROAD-DPC) database (years 2012-2016), the 30-day mortality of Killip class IV AMI patients (n=21,823) was 42.3%. Multivariate analysis identified age, female sex, admission by ambulance, deep coma, and cardiac arrest as patient factors that were independently associated with higher 30-day mortality, and the numbers of JCS board-certified members and of intra-aortic balloon pumping (IABP) cases per year as institutional factors that were independently associated with lower mortality in Killip class IV patients, although IABP was associated with higher mortality in Killip classes I-III patients. Among hospitals with the highest quartile (≥9 JCS board-certified members), the 30-day mortality of Killip class IV patients was 37.4%. Conclusions A higher numbers of JCS board-certified members was associated with better survival of Killip class IV AMI patients. This finding may provide a clue to optimizing local emergency medical services for better management of AMI patients in Japan.

Background: The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia” (FH) as a phenotype with the highest cardiovascular risk. However, whether this criteria could appropriately stratify a high-risk Japanese patient with FH remains unknown. Objectives: This study sought to characterize atherosclerotic cardiovascular diseases in IAS-defined Japanese subjects with severe FH. Methods: This study analyzed 380 clinically diagnosed subjects with heterozygous FH without any history of atherosclerotic cardiovascular diseases. Severe FH was defined as untreated low-density lipoprotein cholesterol >400 mg/dL, >310 mg/dL plus 1 high-risk feature, or >190 mg/dL plus 2 high-risk features according to IAS-proposed statement. The occurrence of first and subsequent composite outcomes (cardiac [cardiac death + coronary artery disease + coronary revascularization] and noncardiac events [stroke + peripheral artery disease] was compared between subjects with severe (n = 135) and non-severe (n = 227) FH. Results: Severe FH was identified in 40.3% of study population. They had higher low-density lipoprotein cholesterol (P < 0.001) and lipoprotein(a) (P = 0.03) levels. Moreover, they more frequently received high-intensity statin (P < 0.001), PCSK9 inhibitor (P < 0.001), and lipoprotein apheresis (P = 0.01) than nonsevere FH subjects did, which resulted in a lower on-treatment low-density lipoprotein cholesterol level of subjects with severe FH (113 ± 47.2 vs 130 ± 53.9 mg/dL; P = 0.007). However, during the 7.4-year observational period, subjects with severe FH exhibited a 9.3-, 15.4-, and 5.9-fold greater risk for first composite (P < 0.001), cardiac (P < 0.001), and noncardiac outcomes (P = 0.02), respectively. Multivariate Cox proportional hazard model consistently revealed the 7.8- and 7.9-fold elevated risks of first (P < 0.001) and of subsequent (P < 0.001) composite outcomes in subjects with severe FH. Conclusions: Japanese subjects with severe FH present profound risks of both first and subsequent atherosclerotic cardiovascular diseases in the primary prevention settings. These findings support the clinical applicability of IAS-defined severe FH in Japanese patients, which identifies those who require further stringent antiatherosclerotic management.

Next-generation DNA sequencing (NGS) in short-read mode has been recently used for genetic testing in various clinical settings. NGS data accuracy is crucial in clinical settings, and several reports regarding quality control of NGS data, focusing mostly on establishing NGS sequence read accuracy, have been published thus far. Variant calling is another critical source of NGS errors that remains mostly unexplored despite its established significance. In this study, we used a machine-learning-based method to establish an exome-wide benchmark of difficult-to-sequence regions using 10 genome sequence features on the basis of real-world NGS data accumulated in The Genome Aggregation Database (gnomAD) of the human reference genome sequence (GRCh38/hg38). We used the obtained metrics, designated “UNMET score,” along with other lines of structural information of the human genome to identify difficult-to-sequence genomic regions using conventional NGS. Thus, the UNMET score could provide appropriate caveats to address potential sequential errors in protein-coding exons of the human reference genome sequence GRCh38/hg38 in clinical sequencing.

Background We investigated the impact of the ring finger protein 213 p.R4810K variant, a founder variant for moyamoya disease in East Asians, on endovascular therapy outcomes in patients with acute anterior‐circulation large‐vessel occlusion stroke in comparison with noncarriers. Methods Of the consecutive patients with ischemic stroke admitted to our institute from 2011 to 2021, patients who underwent endovascular therapy for acute occlusion of the intracranial internal carotid artery or M1 segment of the middle cerebral artery were included. Outcomes were instant reocclusion, final modified Thrombolysis in Cerebral Infarction reperfusion ≥2b, and early reocclusion. Instant reocclusion was defined as the occurrence of reocclusion during the procedure, and early reocclusion was defined as reocclusion detected on magnetic resonance angiography within 2 weeks after the confirmation of successful reperfusion. Results Of the 277 patients analyzed (128 women; median age, 76 years), 10 patients (3.6%) carried the ring finger protein 213 p.R4810K variant. Variant carriers were younger ( P =0.01) and more frequently had intracranial atherosclerotic disease‐related large‐vessel occlusion as a cause of acute large‐vessel occlusion ( P P P =0.22). Early reocclusion was more frequent in variant carriers compared with noncarriers (60.0% versus 0.4%; P Conclusions Instant and early reocclusions were more frequent in variant carriers who underwent endovascular therapy for acute anterior‐circulation large‐vessel occlusion compared with noncarriers.

Background We investigated the impact of the p.R4810K variant of RNF213 (ring finger protein 213) gene, a susceptibility gene of moyamoya disease in East Asia, on the outer diameter of cervical parts of carotid and vertebral arteries (VAs). Methods We examined consecutive Japanese patients with ischemic stroke who underwent carotid ultrasonography between 2015 and 2019. Patient background and the carotid ultrasonography‐measured outer diameter of extracranial cervical arteries, including the common carotid artery, internal carotid artery, external carotid artery, and cervical VA, were compared between variant carriers and noncarriers. Outer diameters of each artery were defined as the mean distance from far to near wall adventitia of right and left target arteries using carotid ultrasonography. The average diameter of both cervical portions of common carotid arteries, internal carotid arteries, external carotid arteries, and the dominant side diameter of both cervical VAs were used. Results Of the 617 adult patients (204 women; median age, 74 years) analyzed, 26 (4.2%) carried the RNF213 p.R4810K variant. Variant carriers were significantly younger ( P P Conclusion RNF213 p.R4810K variant carriers have smaller cervical arterial outer diameters in both anterior and posterior circulations than noncarriers with ischemic stroke. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02251665.

In asymptomatic patients with mitral regurgitation (MR), data of exercise-induced pulmonary hypertension (EIPH) are limited, and feasibility of evaluating EIPH is not high. We aimed to investigate prognostic impact of EIPH and its substitute parameters. Exercise stress echocardiography (ESE) were performed in 123 consecutive patients with moderate to severe degenerative MR. The endpoint was a composite of death, hospitalization for heart failure, and worsening of symptoms. EIPH [tricuspid regurgitation peak gradient (TRPG) at peak workload ≥ 50 mmHg] was shown in 57 patients (46%). TRPG at low workload was independently associated with TRPG at peak workload (β = 0.67, p

Background Although screening for coronary artery disease (CAD) using computed tomography coronary angiography in patients with stable chest pain has been reported to be beneficial, patients with chronic kidney disease (CKD) might have limited benefit due to complications of contrast agent nephropathy and decreased diagnostic accuracy as a result of coronary artery calcifications. Cardiac magnetic resonance (CMR) has emerged as a novel imaging modality for detecting coronary stenosis and high-risk coronary plaques without contrast media that is not affected by coronary artery calcification. However, the clinical use of this technology has not been robustly evaluated. Methods AQUAMARINE-CKD is an open parallel-group prospective multicenter randomized controlled trial of 524 patients with CKD at high risk for CAD estimated based on risk factor categories for a Japanese urban population (Suita score) recruited from 6 institutions. Participants will be randomized 1:1 to receive a CMR examination that includes non-contrast T1-weighted imaging and coronary magnetic angiography (CMR group) or standard examinations that include stress myocardial scintigraphy (control group). Randomization will be conducted using a web-based system. The primary outcome is a composite of cardiovascular events at 1 year after study examinations: all-cause death, death from CAD, nonfatal myocardial infarction, nonfatal ischemic stroke, and ischemia-driven unplanned coronary intervention (percutaneous coronary intervention or coronary bypass surgery). Discussion If the combination of T1-weighted imaging and coronary magnetic angiography contributes to the risk assessment of CAD in patients with CKD, this study will have major clinical implications for the management of patients with CKD at high risk for CAD. Trial registration Japan Registry of Clinical Trials (jRCT) 1,052,210,075. Registered on September 10, 2021.

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 The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability. Methods and results Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves. Conclusion In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.

Background: Quality indicators (QIs) are an accepted tool for measuring a hospital’s performance in routine care. We examined national trends in adherence to the QIs developed by the Close The Gap-Stroke program by combining data from the health insurance claims database and electronic medical records, and the association between adherence to these QIs and early outcomes in patients with acute ischemic stroke in Japan. Methods: In the present study, patients with acute ischemic stroke who received acute reperfusion therapy in 351 Close The Gap-Stroke-participating hospitals were analyzed retrospectively. The primary outcomes were changes in trends for adherence to the defined QIs by difference-in-difference analysis and the effects of adherence to distinct QIs on in-hospital outcomes at the individual level. A mixed logistic regression model was adjusted for patient and hospital characteristics (eg, age, sex, number of beds) and hospital units as random effects. Results: Between 2013 and 2017, 21 651 patients (median age, 77 years; 43.0% female) were assessed. Of the 25 defined measures, marked and sustainable improvement in the adherence rates was observed for door-to-needle time, door-to-puncture time, proper use of endovascular thrombectomy, and successful revascularization. The in-hospital mortality rate was 11.6%. Adherence to 14 QIs lowered the odds of in-hospital mortality (odds ratio [95% CI], door-to-needle Conclusions: We demonstrated national marked and sustainable improvement in adherence to door-to-needle time, door-to-puncture time, and successful reperfusion from 2013 to 2017 in Japan in patients with acute ischemic stroke. Adhering to the key QIs substantially affected in-hospital outcomes, underlining the importance of monitoring the quality of care using evidence-based QIs and the nationwide Close The Gap-Stroke program.

Background Discrimination is an important determinant of negative mental health outcomes. This study determined the association between the experience of COVID-19-related discrimination and psychological distress among healthcare workers (HCWs) in Japan. Methods This cross-sectional study conducted a health survey among 5703 HCWs of six national medical and research centers in Japan from October 2020 to March 2021. COVID-19-related discrimination was defined either when participants or their family members were badmouthed or when they felt discriminated against in some way. We used the Kessler Psychological Distress Scale (K6) to assess the presence of severe psychological distress (≥ 13 points). We used logistic regression models to examine the association between discrimination and psychological distress. We also identified factors associated with discrimination. Results Of the participants, 484 (8.4%) reported COVID-19-related discrimination and 486 (8.5%) had severe psychological distress. HCWs who were female vs. male (adjusted odds ratio [AOR] = 1.41, 95% confidence interval [CI] = 1.28–1.55), had high vs. low viral exposure (AOR = 2.31, 95% CI = 1.81–2.93), and worked for 11 or more hours/day vs. 8 or less hours/day (AOR = 1.42, 95% CI = 1.35–1.49) were more likely to have experienced COVID-19-related discrimination. The AOR (95% CI) of severe psychological distress was 1.83 (1.29–2.59) among those who experienced discrimination. In the stratified analysis by sociodemographic and job-related factors, all the interactions did not reach statistical significance (p for interaction > 0.20). Conclusion Experience of COVID-19-related discrimination was associated with severe psychological distress among HCWs. During the pandemic, effective measures should be taken to prevent the development of negative mental health outcomes in HCWs who experience discrimination.

Poststroke epilepsy is a major ischaemic/haemorrhagic stroke complication. Seizure recurrence risk estimation and early therapeutic intervention are critical, given the association of poststroke epilepsy with worse functional outcomes, quality of life and greater mortality. Several studies have reported risk factors for seizure recurrence; however, in poststroke epilepsy, the role of EEG in predicting the risk of seizures remains unclear. This multicentre observational study aimed to clarify whether EEG findings constitute a risk factor for seizure recurrence in patients with poststroke epilepsy. Patients with poststroke epilepsy were recruited from the PROgnosis of POst-Stroke Epilepsy study, an observational multicentre cohort study. The enrolled patients with poststroke epilepsy were those admitted at selected hospitals between November 2014 and June 2017. All patients underwent EEG during the interictal period during admission to each hospital and were monitored for seizure recurrence over 1 year. Board-certified neurologists or epileptologists evaluated all EEG findings. We investigated the relationship between EEG findings and seizure recurrence. Among 187 patients with poststroke epilepsy (65 were women with a median age of 75 years) admitted to the lead hospital, 48 (25.7%) had interictal epileptiform discharges on EEG. During the follow-up period (median, 397 days; interquartile range, 337–450 days), interictal epileptiform discharges were positively correlated with seizure recurrence (hazard ratio, 3.82; 95% confidence interval, 2.09–6.97; P < 0.01). The correlation remained significant even after adjusting for age, sex, severity of stroke, type of stroke and generation of antiseizure medications. We detected periodic discharges in 39 patients (20.9%), and spiky/sharp periodic discharges were marginally associated with seizure recurrence (hazard ratio, 1.85; 95% confidence interval, 0.93–3.69; P = 0.08). Analysis of a validation cohort comprising 187 patients with poststroke epilepsy from seven other hospitals corroborated the association between interictal epileptiform discharges and seizure recurrence. We verified that interictal epileptiform discharges are a risk factor for seizure recurrence in patients with poststroke epilepsy. Routine EEG may facilitate the estimation of seizure recurrence risk and the development of therapeutic regimens for poststroke epilepsy.

We conducted a randomized, crossover trial to compare intermittent-scanning continuous glucose monitoring (isCGM) device with structured education (Intervention) to self-monitoring of blood glucose (SMBG) (Control) in the reduction of time below range.This crossover trial involved 104 adults with type 1 diabetes mellitus (T1DM) using multiple daily injections. Participants were randomly allocated to either sequence Intervention/Control or sequence Control/Intervention. During the Intervention period which lasted 84 days, participants used the first-generation FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA) and received structured education on how to prevent hypoglycemia based on the trend arrow and by frequent sensor scanning (≥10 times a day). Confirmatory SMBG was conducted before dosing insulin. The Control period lasted 84 days. The primary endpoint was the decrease in the time below range (TBR;70 mg/dL).The time below range was significantly reduced in the Intervention arm compared to the Control arm (2.42 ± 1.68 h/day [10.1 %±7.0 %] vs 3.10 ± 2.28 h/day [12.9 %±9.5 %], P = 0.012). The ratio of high-risk participants with low blood glucose index 5 was significantly reduced (8.6 % vs 23.7 %, P 0.001).The use of isCGM combined with structured education significantly reduced the time below range in patients with T1DM.

Current guidelines equally recommend direct oral anticoagulants (DOACs) and warfarin for atrial fibrillation (AF) patients with a bioprosthetic valve (BPV); however, there are limited data comparing DOACs and warfarin in AF patients with an aortic BPV.Methods and Results: This post-hoc subgroup analysis of a multicenter, prospective, observational registry (BPV-AF Registry) aimed to compare DOACs and warfarin in AF patients with an aortic BPV. The primary outcome was a composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or BPV reoperation. The analysis included 479 patients (warfarin group, n=258; DOAC group, n=221). Surgical aortic valve replacement was performed in 74.4% and 36.7% of patients in the warfarin and DOAC groups, respectively. During a mean follow up of 15.5 months, the primary outcome occurred in 45 (17.4%) and 32 (14.5%) patients in the warfarin and DOAC groups, respectively. No significant difference was found in the primary outcome between the 2 groups (adjusted hazard ratio: 0.88, 95% confidence interval: 0.51-1.50). No significant multiplicative interaction was observed between the anticoagulant effects and type of aortic valve procedure (P=0.577).Among AF patients with an aortic BPV, no significant difference was observed in the composite outcome of adverse clinical events between patients treated with warfarin and those treated with DOACs, suggesting that DOACs can be used as alternatives to warfarin in these patients.

ObjectivesTo evaluate a predictive model for robust estimation of daily out-of-hospital cardiac arrest (OHCA) incidence using a suite of machine learning (ML) approaches and high-resolution meteorological and chronological data.MethodsIn this population-based study, we combined an OHCA nationwide registry and high-resolution meteorological and chronological datasets from Japan. We developed a model to predict daily OHCA incidence with a training dataset for 2005–2013 using the eXtreme Gradient Boosting algorithm. A dataset for 2014–2015 was used to test the predictive model. The main outcome was the accuracy of the predictive model for the number of daily OHCA events, based on mean absolute error (MAE) and mean absolute percentage error (MAPE). In general, a model with MAPE less than 10% is considered highly accurate.ResultsAmong the 1 299 784 OHCA cases, 661 052 OHCA cases of cardiac origin (525 374 cases in the training dataset on which fourfold cross-validation was performed and 135 678 cases in the testing dataset) were included in the analysis. Compared with the ML models using meteorological or chronological variables alone, the ML model with combined meteorological and chronological variables had the highest predictive accuracy in the training (MAE 1.314 and MAPE 7.007%) and testing datasets (MAE 1.547 and MAPE 7.788%). Sunday, Monday, holiday, winter, low ambient temperature and large interday or intraday temperature difference were more strongly associated with OHCA incidence than other the meteorological and chronological variables.ConclusionsA ML predictive model using comprehensive daily meteorological and chronological data allows for highly precise estimates of OHCA incidence.

Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS2°P) is a contemporary risk scoring system for secondary prevention based on nine clinical factors. However, this scoring system has not been validated in other populations. The aim of this study was to validate the TRS2°P in patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI) in a nationwide registry cohort. Among 3283 consecutive patients with AMI enrolled in the Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET), a total of 2611 patients who underwent primary PCI were included in this study. The performance of the TRS2°P to predict major adverse cardiovascular events (MACE) composed of all-cause death, non-fatal MI, and non-fatal stroke up to 3 years in the present cohort was evaluated. The TRS2°P had modest discriminative performance in this J-MINUET cohort with a c-statistic of 0.63, similar to that in the derived cohort (TRA2°P-TIMI50, c-statistic 0.67). A strong graded relationship between the TRS2°P and 3-year cardiovascular event rates was also observed in the J-MINUET cohort. Age ≥ 75 years, Killip ≥ 2, prior stroke, peripheral artery disease, anemia, and non-ST-elevation myocardial infarction were identified as independent factors for the incidence of MACE. The TRS2°P modestly predicted secondary cardiovascular events among patients with AMI treated by primary PCI in a nationwide cohort of Japan. Further studies are needed to develop a novel risk score better predicting secondary cardiovascular events.

OBJECTIVEImproved outcomes in patients with subarachnoid hemorrhage (SAH) treated at high-volume centers have been reported. The authors sought to examine whether hospital case volume and comprehensive stroke center (CSC) capabilities affect outcomes in patients treated with clipping or coiling for SAH.METHODSThe authors conducted a nationwide retrospective cohort study in 27,490 SAH patients who underwent clipping or coiling in 621 institutions between 2010 and 2015 and whose data were collected from the Japanese nationwide J-ASPECT Diagnosis Procedure Combination database. The CSC capabilities of each hospital were assessed by use of a validated scoring system based on answers to a previously reported 25-item questionnaire (CSC score 1–25 points). Hospitals were classified into quartiles based on CSC scores and case volumes of clipping or coiling for SAH.RESULTSOverall, the absolute risk reductions associated with high versus low case volumes and high versus low CSC scores were relatively small. Nevertheless, in patients who underwent clipping, a high case volume (> 14 cases/yr) was significantly associated with reduced in-hospital mortality (Q1 as control, Q4 OR 0.71, 95% CI 0.55–0.90) but not with short-term poor outcome. In patients who underwent coiling, a high case volume (> 9 cases/yr) was associated with reduced in-hospital mortality (Q4 OR 0.69, 95% CI 0.53–0.90) and short-term poor outcomes (Q3 [> 5 cases/yr] OR 0.75, 95% CI 0.59–0.96 vs Q4 OR 0.65, 95% CI 0.51–0.82). A high CSC score (> 19 points) was significantly associated with reduced in-hospital mortality for clipping (OR 0.68, 95% CI 0.54–0.86) but not coiling treatment. There was no association between CSC capabilities and short-term poor outcomes.CONCLUSIONSThe effects of case volume and CSC capabilities on in-hospital mortality and short-term functional outcomes in SAH patients differed between patients undergoing clipping and those undergoing coiling. In the modern endovascular era, better outcomes of clipping may be achieved in facilities with high CSC capabilities.

Although gender difference in long-term outcomes after acute myocardial infarction have been shown previously, impact of age on gender difference is still controversial. This study focused on the association between age and gender difference in long-term outcome. We analyzed data from 3,283 consecutive patients who were included in a prospective, nationwide, multicenter registry (Japan Registry of Acute Myocardial Infarction Diagnosed by Universal Definition) from 2012 to 2014. The primary end point was the major adverse cardiovascular event (MACE), which was defined as a composite of death, myocardial infarction, stroke, heart failure, and revascularization for unstable angina during 3 years. Patients were divided into 4 strata according to age: those with age65 years (group 1: n = 1161), 65 to 74 years (group 2: n = 954), 75 to 84 years (group 3: n = 866) and 84years (group 4: n = 302). Although the crude incidence of 3-year MACE was significantly higher in women than men (36.4% vs. 28.5%, p0.001), there was not significant gender difference in each group (group 1, 19.6% vs 19.0%, p = 0.74; group 2, 33.1% vs 28.3%, p = 0.25; group 3, 38.9% vs 39.6%, p = 0.54; and group 4, 54.0% vs 56.8%, p = 0.24). In conclusion, although women had higher crude incidence of 3-year MACE than men, there was no gender difference in each group.

Patients with underlying medical conditions are at high risk of developing serious symptoms of the coronavirus disease 2019 than healthy individuals; therefore, it is necessary to evaluate the immune response to vaccination among them to formulate precision and personalized vaccination strategies. However, inconsistent evidence exists regarding whether patients with underlying medical conditions have lower anti-SARS-CoV-2 spike IgG antibody titers. We performed a cross-sectional study enrolling 2762 healthcare workers who received second doses of BNT162b2 vaccination from three medical and research institutes between June and July, 2021. Medical conditions were surveyed by a questionnaire, and spike IgG antibody titers were measured with chemiluminescent enzyme immunoassay using serum collected on the median of 62 days after the second vaccination. Multilevel linear regression model was used to estimate geometric mean and ratio of mean (95% confidence interval, CI) for the presence and absence of medical conditions and treatments. Among all participants (median age, 40 years [interquartile range, 30–50]; male proportion, 29.4%), the prevalence of hypertension, diabetes, chronic lung disease, cardiovascular disease, and cancer was 7.5%, 2.3%, 3.8%, 1.8%, and 1.3%, respectively. Patients with treated hypertension had lower antibody titers than those without hypertension; the multivariable-adjusted ratio of mean (95% CI) was 0.86 (0.76–0.98). Patients with untreated and treated diabetes had lower antibody titers than those without diabetes; the multivariable-adjusted ratio of mean (95% CI) was 0.63 (0.42–0.95) and 0.77 (0.63–0.95), respectively. No substantial difference was observed between the presence or absence of chronic lung disease, cardiovascular disease, or cancer. Patients with untreated hypertension and patients with untreated and treated diabetes had lower spike IgG antibody titers than participants without those medical conditions, suggesting that continuous monitoring of antibody titers and further booster shots could be necessary to maintain adaptive immunity in patients with hypertension or diabetes.

ObjectivesTo examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan.DesignRetrospective study.SettingSix hundred and thirty-one primary care institutions in Japan.ParticipantsForty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database.Primary and secondary outcome measuresAnnual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3–6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1–25 points).ResultsIn the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality.ConclusionsThe 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.

ImportanceChronic hemodynamically significant aortic regurgitation (AR) is associated with excess risk of death, yet data for Asian patients are lacking, and whether Asian patients can abide by Western guidelines as to when aortic valve surgery should be performed is unknown.ObjectiveTo assess AR presentation and cutoffs of left ventricular ejection fraction (LVEF), LV end-systolic dimension index (LVESDi), and LV end-systolic volume index (LVESVi) that are associated with risk of death in Asian patients with AR.Design, Setting, and ParticipantsThis retrospective cohort study included consecutive patients with chronic, moderately severe to severe AR from 3 tertiary referral centers (2 in Japan and 1 in Taiwan) from June 11, 2008, through November 19, 2020, with follow-up through November 11, 2021.ExposuresAortic regurgitation severity, graded by a comprehensive integrated approach.Main Outcomes and MeasuresThe primary outcome was the association between volume-derived LVEF, LVESDi, and LVESVi and all-cause death (ACD). The secondary outcome was the association of these LV indexes with cardiovascular death (CVD). Clinical and echocardiographic data were analyzed retrospectively. A de novo disk-summation method was used to derive LV volumes and volume-derived LVEF.ResultsOf 1259 patients (mean [SD] age, 64 [17] years; 934 [74%] male), 515 (41%) were Japanese and 744 (59%) were Taiwanese. The median follow-up was 4.1 years (IQR, 1.56-7.24 years). The mean (SD) body surface area was 1.67 (0.21) m2; LVEF, 55% (11%); LVESDi, 24.7 (5.7) mm/m2; LVESVi, 50.1 (28.0) mL/m2; and indexed mid–ascending aorta size, 24.7 (5.5) mm/m2. Aortic valve surgery occurred in 483 patients (38%); 240 patients (19%) died during follow-up. Overall mean (SD) 8-year survival was 74% (2%). Separate multivariate models adjusted for covariates demonstrated independent associations of LVEF, LVESDi, and LVESVi with ACD (LVEF: hazard ratio [HR] per 10%, 0.80; 95% CI, 0.70-0.92; P = .002; LVESDi: HR, 1.04; 95% CI, 1.01-1.06; P = .002; LVESVi: HR per 10 mL/m2, 1.11; 95% CI, 1.05-1.17; P P P = .01; LVESVi per 10 mL/m2: HR, 1.15; 95% CI, 1.06-1.24; P 2 or greater, and LVESVi of 46 mL/m2 or greater for both ACD and CVD. Early surgery was beneficial in 3 strata of LVESDi (2) and 2 strata of LVESVi (2).Conclusions and RelevanceThis multicenter cohort study of Asian patients with hemodynamically significant AR found cutoff values of LVEF, LVESDi, and LVESVi that were associated with increased risk of death. These findings suggest that Western guidelines seem applicable in Asian patients and, most importantly, that indexed LV parameters with a lower cutoff could be used in discriminating patients with excess mortality risk.

Calcified nodule (CN) is an eruptive calcified mass causing acute coronary syndrome (ACS). Since coronary calcification is associated with an elevated cardiac event's risk, ACS attributable to CN may exhibit worse clinical outcome following percutaneous coronary intervention (PCI).We retrospectively analyzed 657 ACS patients receiving PCI with newer-generation drug-eluting stent (DES) implantation under intravascular ultrasound (IVUS) guidance. CN was defined as (1) protruding calcification with its irregular surface and (2) the presence of calcification at adjacent proximal and distal segments. The primary endpoint was a composite of major adverse cardiac event [MACE = cardiac death + ACS recurrence + target lesion revascularization (TLR)].CN was identified in 5.3% (=35/657) of the study subjects. CN patients were more likely to have coronary risk factors including hypertension (p = 0.005), chronic kidney disease (p 0.001), maintenance hemodialysis (p 0.001) and a history of PCI (p 0.001). During the observational period (median = 1304 days), CN was associated with an increased risk of MACE (HR = 7.68, 95%CI = 4.61-12.80, p 0.001), ACS recurrence (HR = 12.32, 95%CI = 6.05-25.11, p 0.001) and TLR (HR = 10.48, 95%CI = 5.80-18.94, p 0.001). These cardiac risks related to CN were consistently observed by Cox proportional hazards model (MACE: p 0.001, ACS recurrence: p 0.001, TLR: p 0.001) and a propensity score-matched cohort analysis (MACE: p = 0.002, ACS recurrence: p = 0.01, TLR: p = 0.005). Of note, over 80% of TLR at the CN lesion was driven by its re-appearance within the implanted DES.ACS patients attributable to CN have an increased risk of ACS recurrence and TLR, mainly driven by the continuous growth and protrusion of the calcified mass.

BACKGROUND In Japan there is no consensus on how to efficiently measure quality indicators (QIs), defined as a standard of care, for acute ischemic stroke (AIS). Using information from a health insurance claims database and electronic medical records, we evaluated the feasibility and validity of measuring QIs for AIS patients who received intravenous recombinant tissue plasminogen activator (IV rt-PA) or endovascular therapy (EVT).Methods and Results:AIS patients receiving rt-PA or EVT between 2013 and 2015 were identified. We selected 17 AIS QI measures for primary stroke centers (PSCs) and 8 for comprehensive stroke centers (CSCs). Defined QIs were calculated for each hospital and then averaged. In total, the data of 8,206 patients (rt-PA 83.7%, EVT 34.9%) from 172 hospitals were obtained. Median National Institute of Health Stroke Scale score at admission was 14, and 37.7% of the patients were functionally independent at discharge. All target QIs were successfully measured with fewer missing values, and the accuracy of preset data was about 90%. Adherence rates were low (