Combined Prognostic Impact of Two Quick Frailty Assessments in Acute Heart Failure.

INTRODUCTION: We aimed to investigate the prognostic impact of frailty (defined by the Study of Osteoporotic Fracture [SOF] index and the Clinical Frailty Scale [CFS]) in hospitalized patients with acute decompensated heart failure (HF). METHODS: A total of 1,053 patients over 75 years of age, who were primarily admitted to hospital with a diagnosis of acute decompensated HF, were enrolled. The prognostic value of frailty by the two tools for predicting all-cause mortality was analyzed using multivariate Cox regression models. RESULTS: The incidence of frailty was 57.1% when using the SOF index, 37.6% when using the CFS, and 23.3% when using both tools. Frailty, via the SOF index or CFS, was an independent predictor of all-cause mortality in model 1, after adjustment for significantly associated factors by univariate analysis (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.04-1.84, p = 0.027; HR 1.53, 95% CI 1.15-2.05, p = 0.003, respectively), and in model 2, after adjustment for previously reported prognostic factors (HR 1.42, 95% CI 1.07-1.89, p = 0.015; HR 1.56, 95% CI 1.17-2.07, p = 0.002, respectively). Compared to non-frail patients, frail patients via both tools had a significantly higher incidence of all-cause mortality in models 1 (adjusted HR 2.16, 95% CI 1.42-3.29, p < 0.001) and 2 (adjusted HR 2.30, 95% CI 1.51-3.50, p < 0.001). CONCLUSIONS: Combined frailty screening using the SOF index and CFS contributed to stratify the risk of mortality in patients with acute decompensated HF.

Safety of clinical engineer-assisted percutaneous coronary intervention.

Percutaneous coronary intervention (PCI) requires multiple staff members, including interventional cardiologists, with the physical burden of heavy protective measures to minimize radiation exposure. Here, we aimed to investigate the safety of task sharing with clinical engineers (CEs) working as 1st assistant during ad hoc PCI. We retrospectively included 286 patients who underwent ad hoc PCI following diagnostic catheterization for coronary artery disease between April 2019 and March 2021. Procedural complications including coronary perforation or rupture, myocardial infarction, cerebral embolism, cardiovascular death, decreased kidney function, and radiation parameters were compared between the two clinical settings [CE group, CEs as the 1st assistant from the beginning of diagnostic coronary angiography to the end of PCI vs. doctor (DR) group, others]. There was no increase in the ratio of procedural complications in the CE group (1.7%) versus the DR group (1.2%). Fluorescence time and radiation exposure dose were significantly reduced in the CE group {25 min [interquartile range (IQR), 19-35 min] vs. 28 min (IQR, 20-39 min), P = 0.036; 908 mGy (IQR, 654-1326 mGy) vs. 1062 mGy (IQR, 732-1594 mGy), P = 0.049}. The median amount of contrast medium was significantly reduced in the CE group [100 mL (IQR, 80-119 mL) vs. 110 mL (IQR 90-140 mL), P < 0.001]. After propensity matching, fluorescence time, radiation exposure dose, and contrast medium amount were similar between groups. Task sharing with CEs as the 1st assistant during ad hoc PCI could contribute to clinical safety in patients with coronary artery disease.

Prognostic efficacy of a post-discharge visiting program for patients with heart failure.

We aimed to investigate the impact of post-discharge scheduled hospital visits on readmission due to heart failure (HF). In this retrospective study, a total of 245 patients (N = 101 in the scheduled hospital visit group, N = 144 in the non-scheduled hospital visit group) who were alive with free from readmission due to HF for 90 days after discharge were enrolled. The patients had been hospitalized with acute decompensated HF between August 2018 and July 2019. Scheduled hospital visits were recommended 90 days after the patients had been discharged. After checking their self-care adherence, nurse-led self-care maintenance and monitoring were provided. To determine the effectiveness of the scheduled hospital visits, we conducted landmark analyses divided into two periods: Scheduled visits within 180 days, and after 180 days. The readmission rate due to HF within 180 days was lower in the scheduled visit group. In the landmark analysis, the 1-year incidence rate of readmission was significantly lower in patients with a scheduled hospital visit than in those without, in the period within 180 days (2.0% vs 9.0%, P = 0.029) but not after 180 days. After adjusting for age and estimated glomerular filtration rate as confounders, scheduled hospital visits tended to reduce readmission due to HF (P = 0.060); however, readmission was significantly reduced in the period within 180 days (P = 0.007). In conclusion, scheduled hospital visits at 90 days after discharge may be beneficial in delaying readmission due to HF by reducing risk of readmission during the early post-visit period.

Regional left atrial conduction velocity in the anterior wall is associated with clinical recurrence of atrial fibrillation after catheter ablation: efficacy in combination with the ipsilateral low voltage area.

BACKGROUND: Left atrial (LA) conduction velocity (CV) is an electrical remodeling parameter of atrial fibrillation (AF) substrate. However, the pathophysiological substrate of LA-CV and its impact on outcomes after catheter ablation for AF have not been well evaluated. METHODS: We retrospectively evaluated 119 patients with AF who underwent catheter ablation and electroanatomical mapping during sinus rhythm. To measure regional LA-CV, we took triplet sites (A, B, and C) on the activation map and calculated the magnitude of the matched orthogonal projection vector between vector-AB and vector-AC, indicating two-dimensional CV. The median of the LA-CVs from four triad sites in both the anterior and posterior walls was set as the 'model LA-CV'. We evaluated the impact of the model LA-CV on recurrence after ablation and relationship between the model LA-CV and LA-low voltage area (LVA) of < 0.5 mV. RESULTS: During the 12-month follow-up, 29 patients experienced recurrence. The LA-CV model was significantly correlated with ipsilateral LVA. The lower anterior model LA-CV was significantly associated with recurrence, with the cut-off value of 0.80 m/s having a sensitivity of 72% and specificity of 67%. Multivariable analysis revealed that the anterior model LA-CV (hazard ratio, 0.09; 95% confidence interval, 0.01-0.94; p = 0.043) and anterior LA-LVA (hazard ratio, 1.06; 95% confidence interval, 1.00-1.11; p = 0.033) were independently associated with AF recurrence. The anterior LA-LVA was mildly correlated with the anterior model LA-CV (r = -0.358; p < 0.001), and patients with both lower LA-CV and greater anterior LA-LVA based on each cut-off value had the worst prognosis. However, decreased LA-CV was more likely to be affected by the distribution pattern of the LVA rather than the total size of the LVA. CONCLUSION: Decreased anterior LA-CV was a significant predictor of AF recurrence and was a useful electrical parameter in addition to LA-LVA for estimating AF arrhythmogenicity.

Outcomes and Safety of Very-Low-Dose Edoxaban in Frail Patients With Atrial Fibrillation in the ELDERCARE-AF Randomized Clinical Trial.

Importance: The prevalence of atrial fibrillation (AF) increases with age and is more common in frail patients. However, data are lacking on outcomes of oral anticoagulants (OACs) in very elderly patients with AF with frailty, who are ineligible for standard anticoagulant treatment. Objective: To compare very-low-dose edoxaban (15 mg daily) vs placebo across frailty status, including each of 5 frailty assessment parameters, among patients with AF involved in the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial. Design, Setting, and Participants: This is a cohort study using data from ELDERCARE-AF, a multicenter, randomized, double-blind, placebo-controlled phase 3 study of Japanese patients with AF aged 80 years or older who were ineligible for OACs at doses approved for stroke prevention because of their high bleeding risks. Eligible patients were randomly assigned (1:1) to receive edoxaban or placebo. The study duration was from August 5, 2016, to November 5, 2019, with the last patient followed up on December 27, 2019. Data analysis was performed from February 2021 to February 2022. Exposure: Edoxaban (15 mg) once daily or placebo. Main Outcomes and Measures: The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding. Results: A total of 984 patients were randomly assigned to treatment (492 each to the edoxaban and placebo groups); 944 patients (402 frail patients [42.6%]; 542 nonfrail patients [57.4%]; mean [SD] age, 86.6 [4.3] years; 541 women [57.3%]) were included in this analysis. In the placebo group, the estimated event rates (SE) for stroke or systemic embolism were 7.1% (1.6%) per patient-year in the frail group and 6.1% (1.3%) per patient-year in the nonfrail group. Edoxaban was associated with lower event rates for stroke or systemic embolism with no interaction with frailty status or frailty assessment parameters. Major bleeding and major or clinically relevant nonmajor bleeding events were both numerically higher in the edoxaban group than in the placebo group, and no heterogeneity was observed with frailty status. Although both all-cause death and net clinical composite outcome occurred more frequently in the frail group than in the nonfrail group, there was no association with frailty status between the edoxaban and placebo groups. Conclusions and Relevance: Regardless of frailty status, among Japanese patients with AF aged 80 years or older who were ineligible for standard OACs, once-daily 15-mg edoxaban was associated with reduced incidence of stroke or systemic embolism and may be a suitable treatment option for these patients.

Long-Term Effect of Febuxostat on Endothelial Function in Patients With Asymptomatic Hyperuricemia: A Sub-Analysis of the PRIZE Study.

Background: Xanthine oxidase is involved in the production of uric acid and the generation of superoxide anion. We evaluated the long-term effect of febuxostat, a non-purine selective xanthine oxidase inhibitor, on endothelial function in patients with asymptomatic hyperuricemia. Methods: In the PRIZE study, patients with hyperuricemia were randomly assigned to either add-on febuxostat treatment (febuxostat group) or non-pharmacologic hyperuricemia treatment (control group). Among the 514 participants, endothelial function was assessed in 41 patients in the febuxostat group and 38 patients in the control group by flow-mediated vasodilation (FMD) of the brachial artery at the beginning of the study and after 12 and/or 24 months of treatment (63 men; median age, 68.0 years). Results: The least squares mean concentration of serum uric acid was significantly lower in the febuxostat group than in the control group at 6 months (mean between-group difference [febuxostat group - control group], -2.09 mg/dL [95% confidence interval (CI), -2.520 to -1.659]; P < 0.001), 12 months (mean between-group difference, -2.28 mg/dL [95% CI, -2.709 to -1.842]; P < 0.001), and 24 months (mean between-group difference, -2.61 mg/dL [95% CI, -3.059 to -2.169]; P < 0.001). No significant differences were found between groups in the least squares mean estimated percentage change in FMD at 12 months (mean between-group difference, -0.56% [95% CI, -1.670 to 0.548]; P = 0.319) and at 24 months (mean between-group difference, -0.60% [95% CI, -1.886 to 0.685]; P = 0.357). Conclusion: Febuxostat treatment did not alter endothelial function assessed by FMD during a 2-year study period in patients with asymptomatic hyperuricemia.

Long P-wave duration immediately after pulmonary vein isolation on radiofrequency catheter ablation for atrial fibrillation predicts clinical recurrence: correlation with atrial remodeling in persistent atrial fibrillation.

P-wave morphology reflects atrial remodeling and indicates prognosis after radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF). The impact of p-wave morphology after excluding the effect of pulmonary vein (PV) substrate on outcomes is unknown. We evaluated the p-wave morphology on electrocardiography immediately after PV isolation for clinical outcomes. Eighty-four consecutive patients (47 with paroxysmal AF and 37 with persistent AF) who underwent RFCA were included. P-wave duration (PWD) and amplitude in all leads were examined during sinus rhythm immediately after PV isolation. We evaluated the relationship between electrocardiogram parameters and AF recurrence, according to the type of AF and following ablation, and the correlation with left atrial (LA) volume, low voltage ratio, and fixed conduction time. During 12 months of follow-up, 20 patients experienced recurrence. The cut-off value of PWD > 120 ms in lead I showed a sensitivity of 75% and specificity of 69% for predicting recurrence. PWD was significantly correlated with LA volume, low voltage, and conduction velocity. Significantly higher recurrence rates were observed in patients with PWD > 120 ms than in those with PWD ≤ 120 ms (p < 0.001), and the difference was more pronounced in patients with persistent AF. Multivariate analysis demonstrated that PWD > 120 ms was independently associated with recurrence in the total population (hazard ratio 2.00; 95% confidence interval 1.27-3.22; p = 0.003) and in patients with persistent AF. In conclusion, long PWD after PV isolation predicts AF recurrence, which might be associated with the extent of the LA substrate in persistent AF.

Reduction of door-to-balloon time in patients with ST-elevation myocardial infarction by single-catheter primary percutaneous coronary intervention method.

OBJECTIVES: The objectives of this study is to confirm reduction of door-to-balloon (D2B) time with single-catheter percutaneous coronary intervention (SC-PCI) method. BACKGROUND: Reduction of total ischemic time is important in the emergency treatment of ST-elevation myocardial infarction (STEMI). There have been no established methods in primary percutaneous coronary intervention (PCI) to shorten ischemic time via radial access. Ikari left curve was reported as a universal guiding catheter for left and right coronary arteries. Several procedure steps can be skipped by SC-PCI method as the advantage of a universal catheter. METHODS: This study is a retrospective analysis of a total of 1,275 consecutive STEMI cases treated with primary PCI in 14 hospitals. Patients were divided into two groups, SC-PCI method (n = 298) and conventional PCI method (n = 977). Primary endpoints were door-to-balloon (D2B) time and radiation exposure dose. RESULTS: The mean age was 68 ± 13 years old. Radial access was used in 85% of participants. PCI success was achieved in 99.5% of participants and the SC-PCI method was successfully performed in 92.6%. The D2B time was shorter (68 ± 46 vs. 74 ± 50 min, respectively; p = .02), and the radiation exposure dose was lower (1,664 ± 970 vs. 2008 ± 1,605 mGy, respectively; p < .0001) in the SC-PCI group than in the conventional group. CONCLUSION: Primary PCI with SC-PCI method for patients with STEMI demonstrated shorter D2B time and lower radiation exposure dose.

Combined prognostic value of malnutrition using GLIM criteria and renal insufficiency in elderly heart failure.

AIMS: We aimed to investigate the prognostic impact of malnutrition, defined by the Global Leadership Initiative on Malnutrition (GLIM) criteria, stratified by renal function in hospitalized patients with acute decompensated heart failure (HF). METHODS AND RESULTS: In this retrospective study, 314 patients who were hospitalized for acute decompensated HF from August 2019 to October 2020 were enrolled. We evaluated malnutrition using the GLIM criteria during the time of admission. The primary outcome was 90-day all-cause mortality. The median patient age was 82 years, and 90-day mortality was 14.0%. In total, 76 (24.2%) patients were malnourished according to the GLIM criteria. Malnutrition defined by the GLIM criteria [adjusted hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.02-1.91, P = 0.036] and renal insufficiency [adjusted HR 2.59, 95% CI 1.07-6.28, P = 0.035 for estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 vs. ≥60 mL/min/1.73 m2 ] were identified as independent predictors of 90-day mortality after adjustment for age, systolic blood pressure, and serum sodium level. In the combined setting of both variables, patients with malnutrition and eGFR < 30 mL/min/1.73 m2 had a markedly higher risk of 90-day mortality compared with those without malnutrition and eGFR ≥ 60 mL/min/1.73 m2 (adjusted HR 3.92, 95% CI 1.10-13.9, P = 0.035). Adding both eGFR and malnutrition, defined by the GLIM criteria, to the baseline model with established risk factors improved both net reclassification and integrated discrimination greater than that of the baseline model (0.606, P < 0.001 and 0.050, P = 0.002, respectively), even when compared with the model with malnutrition by the GLIM alone (0.463, P = 0.002 and 0.034, P < 0.001, respectively). CONCLUSIONS: Nutrition screening using the GLIM criteria stratified by renal function could clearly predict 90-day mortality in hospitalized patients with acute decompensated HF.

＜Editors' Choice＞ Prognostic utility of multipoint nutritional screening for hospitalized patients with acute decompensated heart failure.

This study aimed to evaluate the impact of serial changes in nutritional status on 1-year events including all-cause mortality or rehospitalization owing to heart failure (HF) among hospitalized patients with acute decompensated HF (ADHF). The study subjects comprised 253 hospitalized patients with ADHF. The controlling nutritional status (CONUT) score was assessed both at hospital admission and discharge. The subjects were divided into three groups according to nutritional status using CONUT score: normal (0 and 1), mild risk (2-4), and moderate to severe risk defined as malnutrition (5-12). We observed nutritional status was improved or not. The incidence of malnutrition was 30.4% at hospital admission and 23.7% at discharge, respectively. Malnutrition was independently associated with 1-year events among hospitalized patients with ADHF. Presence or absence of improvement in nutritional status was significantly associated with 1-year events (P < 0.05), that was independent of percentage change in plasma volume in multivariate Cox regression analyses. We determined a reference model, including gender and estimated glomerular filtration rate, using multivariate logistic regression analysis (P < 0.05). Adding the absence of improvement in nutritional status during hospitalization to the reference model significantly improved both NRI and IDI (0.563, P < 0.001 and 0.039, P = 0.001). Furthermore, malnutrition at hospital discharge significantly improved NRI (0.256, P = 0.036) In conclusion, serial changes in the nutritional status evaluated on the basis of multiple measurements may provide more useful information to predict 1-year events than single measurement at hospital admission or discharge in hospitalized patients with ADHF.

Diagnostic Accuracy of Diastolic Fractional Flow Reserve for Functional Evaluation of Coronary Stenosis: DIASTOLE Study.

Background: In the resting conditions, narrowing the window of coronary pressure measurements from the whole cardiac cycle to diastole improves diagnostic performance of coronary pressure-derived physiological index. However, whether this also applies to the hyperemic conditions has not yet been thoroughly evaluated. Objectives: The purpose of this study was to assess whether diastolic fractional flow reserve (diastolic FFR) has better diagnostic performance in identifying ischemia-causing coronary lesions than conventional FFR in a prospective, multicenter, and independent core laboratory-based environment. Methods: In this prospective multicenter registry at 29 Japanese centers, we compared the diagnostic performance of FFR, diastolic FFR, resting distal to aortic coronary pressure (Pd/Pa), and diastolic pressure ratio (dPR) using myocardial perfusion scintigraphy (MPS) as the reference standard in 378 patients with single-vessel coronary disease. Results: Inducible myocardial ischemia was found on MPS in the relevant myocardial territory of the target vessel in 85 patients (22%). In the receiver-operating curve analyses, diastolic FFR had comparable area under the curve (AUC) compared with FFR (AUCdiastolic FFR: 0.66; 95% confidence interval [CI]: 0.58-0.73, vs AUCFFR: 0.66; 95% CI: 0.58-0.74, P = 0.624). FFR and diastolic FFR showed significantly larger AUCs than resting Pd/Pa (0.62; 95% CI: 0.54-0.70; P = 0.033 and P = 0.046) but did not show significantly larger AUCs than dPR (0.62; 95% CI: 0.55-0.70; P = 0.102 and P = 0.113). Conclusions: Diastolic FFR showed a similar diagnostic performance to FFR as compared with MPS. This result reaffirms the use of FFR as the most accurate invasive physiological lesion assessment. (Diagnostic accuracy of diastolic fractional flow reserve (d-FFR) for functional evaluation of coronary stenosis; UMIN000015906).

Efficacy of Rapid Decongestion Strategy in Patients Hospitalized for Acute Heart Failure.

BACKGROUND: Clinical congestion is the most dominant feature in patients with acute decompensated heart failure (HF). However, uncertainty exists due to the permutations and combinations of congestion status and decongestion strategies. This study investigated the effect of congestion status and its improvement on 1-year mortality.Methods and Results:In all, 453 consecutive patients hospitalized for acute decompensated HF between July 2015 and March 2017 were prospectively included in the study. Congestion was evaluated using the congestion score. The 1-year mortality rate was 22.7%. The mean (±SD) congestion scores at admission, on Day 3, and at discharge were 10.7±3.9, 3.4±3.5, and 0.3±0.8, respectively. The improvement rate in congestion scores during the first 3 days was 78%; 46.6% of patients had residual congestion. The Day 3 congestion score and the improvement rate during the first 3 days were related to 1-year all-cause mortality and cardiovascular mortality. Combined predictive values were examined by calculating multivariable-adjusted hazard ratios for associations of residual congestion and improvement rate during the first 3 days, and prognostic variables identified by the Cox regression model. Residual congestion and lesser improvement (<64%) were associated with higher relative risk of 1-year all-cause mortality and cardiovascular mortality than residual congestion and higher improvement (≥64%) or resolved congestion. CONCLUSIONS: Rapid decongestion could be a prerequisite regardless of residual congestion in hospitalized acute decompensated HF patients.

Evolutionary history of disease-susceptibility loci identified in longitudinal exome-wide association studies.

BACKGROUND: Our longitudinal exome-wide association studies previously detected various genetic determinants of complex disorders using ~26,000 single-nucleotide polymorphisms (SNPs) that passed quality control and longitudinal medical examination data (mean follow-up period, 5 years) in 4884-6022 Japanese subjects. We found that allele frequencies of several identified SNPs were remarkably different among four ethnic groups. Elucidating the evolutionary history of disease-susceptibility loci may help us uncover the pathogenesis of the related complex disorders. METHODS: In the present study, we conducted evolutionary analyses such as extended haplotype homozygosity, focusing on genomic regions containing disease-susceptibility loci and based on genotyping data of our previous studies and datasets from the 1000 Genomes Project. RESULTS: Our evolutionary analyses suggest that derived alleles of rs78338345 of GGA3, rs7656604 at 4q13.3, rs34902660 of SLC17A3, and six SNPs closely located at 12q24.1 associated with type 2 diabetes mellitus, obesity, dyslipidemia, and three complex disorders (hypertension, hyperuricemia, and dyslipidemia), respectively, rapidly expanded after the human dispersion from Africa (Out-of-Africa). Allele frequencies of GGA3 and six SNPs at 12q24.1 appeared to have remarkably changed in East Asians, whereas the derived alleles of rs34902660 of SLC17A3 and rs7656604 at 4q13.3 might have spread across Japanese and non-Africans, respectively, although we cannot completely exclude the possibility that allele frequencies of disease-associated loci may be affected by demographic events. CONCLUSION: Our findings indicate that derived allele frequencies of nine disease-associated SNPs (rs78338345 of GGA3, rs7656604 at 4q13.3, rs34902660 of SLC17A3, and six SNPs at 12q24.1) identified in the longitudinal exome-wide association studies largely increased in non-Africans after Out-of-Africa.

Two novel susceptibility loci for type 2 diabetes mellitus identified by longitudinal exome-wide association studies in a Japanese population.

Recent genome-wide association studies identified genetic variants that confer susceptibility to type 2 diabetes mellitus (T2DM). However, few longitudinal genome-wide association studies of this metabolic disorder have been reported to date. Therefore, we performed a longitudinal exome-wide association study of T2DM, using 24,579 single nucleotide polymorphisms (SNPs) and repeated measurements from 6022 Japanese individuals. The generalized estimating equation model was applied to test relations of SNPs to three T2DM-related parameters: prevalence of T2DM, fasting plasma glucose level, and blood glycosylated hemoglobin content. Three SNPs that passed quality control were significantly (P<2.26×10-7) associated with two of the three T2DM-related parameters in additive and recessive models. Of the three SNPs, rs6414624 in EVC and rs78338345 in GGA3 were novel susceptibility loci for T2DM. In the present study, the SNP of GGA3 was predicted to be a genetic variant whose minor allele frequency has recently increased in East Asia.

Identification of six novel susceptibility loci for dyslipidemia using longitudinal exome-wide association studies in a Japanese population.

Recent genome-wide association studies have identified various dyslipidemia-related genetic variants. However, most studies were conducted in a cross-sectional manner. We thus performed longitudinal exome-wide association studies of dyslipidemia in a Japanese population. We used ~244,000 genetic variants and clinical data of 6022 Japanese individuals who had undergone annual health checkups for several years. After quality control, the association of dyslipidemia-related phenotypes with 24,691 single nucleotide polymorphisms (SNPs) was tested using the generalized estimating equation model. In total, 82 SNPs were significantly (P < 2.03 × 10-6) associated with dyslipidemia phenotypes. Of these SNPs, four (rs74416240 of TCHP, rs925368 of GIT2, rs7969300 of ATXN2, and rs12231744 of NAA25) and two (rs34902660 of SLC17A3 and rs1042127 of CDSN) were identified as novel genetic determinants of hypo-HDL- and hyper-LDL-cholesterolemia, respectively. A replication study using the cross-sectional data of 8310 Japanese individuals showed the association of the six identified SNPs with dyslipidemia-related traits.

Identification of 12 novel loci that confer susceptibility to early-onset dyslipidemia.

The circulating concentrations of triglycerides, high density lipoprotein (HDL)­cholesterol, and low density lipoprotein (LDL)­cholesterol have a substantial genetic component, and the heritability of early­onset dyslipidemia might be expected to be higher compared with late­onset forms. In the present study, exome­wide association studies (EWASs) were performed for early­onset hypertriglyceridemia, hypo­HDL­cholesterolemia, and hyper­LDL­cholesterolemia, with the aim to identify genetic variants that confer susceptibility to these conditions in the Japanese population. A total of 8,073 individuals aged ≤65 years were enrolled in the study. The EWASs for hypertriglyceridemia (2,664 cases and 5,294 controls), hypo­HDL­cholesterolemia (974 cases and 7,085 controls), and hyper­LDL­cholesterolemia (2,911 cases and 5,111 controls) were performed with Illumina Human Exome­12 v1.2 DNA Analysis BeadChip or Infinium Exome­24 v1.0 BeadChip arrays. The association of allele frequencies for 31,198, 31,133, or 31,175 single nucleotide polymorphisms (SNPs) to hypertriglyceridemia, hypo­HDL­cholesterolemia, or hyper­LDL­cholesterolemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with each of the three conditions, Bonferroni's correction was applied for statistical significance of association. The results demonstrated that 25, 28 and 65 SNPs were significantly associated with hypertriglyceridemia, hypo­HDL­cholesterolemia and hyper­LDL­cholesterolemia, respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that all 25, 28 and 65 of these SNPs were significantly associated with hypertriglyceridemia, hypo­HDL­cholesterolemia and hyper­LDL­cholesterolemia, respectively. Following examination of the association of the identified SNPs to serum concentrations of triglycerides, HDL­cholesterol, or LDL­cholesterol, linkage disequilibrium of the SNPs, and results of previous genome­wide association studies, we newly identified chromosomal region 19p12 as a susceptibility locus for hypertriglyceridemia, eight loci (MOB3C­TMOD4, LPGAT1, EHD3, COL6A3, ZNF860­CACNA1D, COL6A5, DCLRE1C, ZNF77) for hypo­HDL­cholesterolemia, and three loci (KIAA0319­FAM65B, UBD, LOC105375015) for hyper­LDL­cholesterolemia. The present study thus identified 12 novel loci that may confer susceptibility to early­onset dyslipidemia. Determination of genotypes for the SNPs at these loci may prove informative for assessment of genetic risk for hypertriglyceridemia, hypo­HDL­cholesterolemia, or hyper­LDL­cholesterolemia in the Japanese population.

Prognostic Importance of Multiple Nutrition Screening Indexes for 1-Year Mortality in Hospitalized Acute Decompensated Heart Failure Patients.

Background: The purpose of the study was to evaluate the impact of nutritional status on 1-year mortality in hospitalized patients with acute decompensated heart failure (ADHF). Methods and Results: We enrolled 457 hospitalized ADHF patients. Previously established objective nutritional indexes (controlling nutritional status [CONUT], prognostic nutritional index [PNI], geriatric nutritional risk index [GNRI], and subjective global assessment [SGA]) were evaluated at hospital admission. Malnutrition was defined as CONUT score ≥5, PNI score <38, GNRI score <92, and SGA scores B and C. The frequencies of malnutrition based on CONUT, PNI, GNRI, and SGA were 31.5%, 21.4%, 44.9%, and 27.8%, respectively. All indexes were related to the occurrence of 1-year mortality on univariate Cox regression analysis (P<0.05). We constructed a reference model using age, body mass index, systolic blood pressure, sodium concentration, and renal function on multivariable Cox regression analysis. Adding SGA to the reference model significantly improved both net reclassification improvement (NRI) and integrated discrimination improvement (0.344, P=0.002; 0.012, P=0.049; respectively). Other indexes (CONUT, PNI, and GNRI scores) significantly improved NRI (0.254, P=0.019; 0.273, P=0.013; 0.306, P=0.006; respectively). Conclusions: Nutritional screening assessed at hospital admission was appropriate for the prediction of 1-year mortality in hospitalized patients with ADHF.

Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population.

Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European populations, genetic variants that contribute toward susceptibility to this condition in Japanese patients remain to be definitively identified. In the present study, exome-wide association studies (EWASs) were performed to identify genetic variants that confer susceptibility to early-onset CAD in Japanese. A total of 7,256 individuals aged ≤65 years were enrolled in the present study. EWAS were conducted on 1,482 patients with CAD and 5,774 healthy controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed using Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The association between allele frequencies for 31,465 SNPs that passed quality control and CAD was examined using Fisher's exact test. To compensate for multiple comparisons of allele frequencies with CAD, a false discovery rate (FDR) of <0.05 was applied for statistically significant associations. The association between allele frequencies for 31,465 SNPs and CAD, as determined by Fisher's exact test, demonstrated that 170 SNPs were significantly (FDR <0.05) associated with CAD. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that 162 SNPs were significantly (P<0.05) associated with CAD. A stepwise forward selection procedure was performed to examine the effects of genotypes for the 162 SNPs on CAD. The 54 SNPs were significant (P<0.05) and independent [coefficient of determination (R2), 0.0008 to 0.0297] determinants of CAD. These SNPs together accounted for 15.5% of the cause of CAD. Following examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, 21 genes (RNF2, YEATS2, USP45, ITGB8, TNS3, FAM170B-AS1, PRKG1, BTRC, MKI67, STIM1, OR52E4, KIAA1551, MON2, PLUT, LINC00354, TRPM1, ADAT1, KRT27, LIPE, GFY and EIF3L) and five chromosomal regions (2p13, 4q31.2, 5q12, 13q34 and 20q13.2) that were significantly associated with CAD were newly identified in the present study. Gene ontology analysis demonstrated that various biological functions were predicted in the 18 genes identified in the present study. The network analysis revealed that the 18 genes had potential direct or indirect interactions with the 30 genes previously revealed to be associated with CAD or with the 228 genes identified in previous genome-wide association studies. The present study newly identified 26 loci that confer susceptibility to CAD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for CAD in Japanese patients.

Identification of 13 novel susceptibility loci for early-onset myocardial infarction, hypertension, or chronic kidney disease.

Early­onset cardiovascular and renal diseases have a strong genetic component. In the present study, exome­wide association studies (EWASs) were performed to identify genetic variants that confer susceptibility to early­onset myocardial infarction (MI), hypertension, or chronic kidney disease (CKD) in Japanese individuals. A total of 8,093 individuals aged ≤65 years was enrolled in the study. The EWASs for MI, hypertension, and CKD were performed in 6,926 subjects (1,152 cases, 5,774 controls), 8,080 subjects (3,444 cases, 4,636 controls), and 2,556 subjects (1,051 cases, 1,505 controls), respectively. Genotyping of single nucleotide polymorphisms (SNPs) was performed with Illumina Human Exome­12 DNA Analysis BeadChip or Infinium Exome­24 BeadChip arrays. The associations of allele frequencies for 31,245, 31,276, or 31,514 SNPs that passed quality control to MI, hypertension, and CKD, respectively, was examined with Fisher's exact test. Bonferroni's correction for statistical significance of association was applied to compensate for multiple comparisons of genotypes with MI, hypertension, or CKD. The EWASs of allele frequencies revealed that 25, 11, and 11 SNPs were significantly associated with MI (P<1.60x10­6), hypertension (P<1.60x10­6), or CKD (P<1.59x10­6), respectively. Multivariable logistic regression analysis with adjustment for covariates showed that all 25, 11, and 11 SNPs were significantly associated with MI (P<0.0005), hypertension (P<0.0011), or CKD (P<0.0011), respectively. On examination of the results from previous genome­wide association studies and linkage disequilibrium of the identified SNPs, 11 loci (TMOD4, COL6A3, ADGRL3­CXCL8­MARCH1, OR52E4, TCHP­GIT2, CCDC63, 12q24.1, OAS3, PLCB2­VPS33B, GOSR2, ZNF77), six loci (MOB3C­TMOD4, COL6A3, COL6A5, CXCL8­MARCH1, NFKBIL1­6p21.3­NCR3, PLCB2­VPS33B), and seven loci (MOB3C­TMOD4, COL6A3, COL6A5, ADGRL3­CXCL8­MARCH1, MUC17, PLCB2­VPS33B, ZNF77) were identified as novel loci significantly associated with MI, hypertension, and CKD, respectively. Furthermore, six genes (TMOD4, COL6A3, CXCL8, MARCH1, PLCB2, VPS33B) were significantly associated with MI, hypertension and CKD; two genes (ADGRL3, ZNF77) with MI and CKD; and two genes (COL6A5, MOB3C) with hypertension and CKD. Therefore, 13 novel loci (MOB3C­TMOD4, COL6A3, ADGRL3­CXCL8­MARCH1, OR52E4, TCHP­GIT2, CCDC63, 12q24.1, OAS3, PLCB2­VPS33B, ZNF77, COL6A5, NFKBIL1­NCR3, MUC17) were identified that confer susceptibility to early­onset MI, hypertension, or CKD. The determination of genotypes for the SNPs at these loci may provide informative for assessment of the genetic risk for MI, hypertension, or CKD.

Hemorrhagic Pericardial Cyst Complicated with Constrictive Pericarditis.

Pericardial cysts are rare abnormalities and are usually asymptomatic. Although several case reports on their diagnosis and treatment have been published, those on hemorrhagic pericardial cysts remain limited. We herein report the case of a 70-year-old man with a hemorrhagic pericardial cyst complicated with constrictive pericarditis 2 years after the initial diagnosis.